Substituted nucleosides, nucleotides and analogs thereof

ABSTRACT

Disclosed herein are nucleotide analogs, methods of synthesizing nucleotide analogs and methods of treating diseases and/or conditions such as a HCV infection with one or more nucleotide analogs.

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

Any and all applications for which a foreign or domestic priority claimis identified in the Application Data Sheet as filed with the presentapplication, are hereby incorporated by reference under 37 CFR 1.57.

REFERENCE TO SEQUENCE LISTING

The present application is being filed along with a Sequence Listing inelectronic format. The Sequence Listing is provided as a file entitledSEQLISTING_(—)65. TXT, created Feb. 13, 2014, which is 1 Kb in size. Theinformation in the electronic format of the Sequence Listing isincorporated herein by reference in its entirety.

BACKGROUND

1. Field

The present application relates to the fields of chemistry, biochemistryand medicine. More particularly, disclosed herein are nucleotideanalogs, pharmaceutical compositions that include one or more nucleotideanalogs and methods of synthesizing the same. Also disclosed herein aremethods of treating diseases and/or conditions with a nucleotide analog,alone or in combination therapy with one or more other agents.

2. Description

Nucleoside analogs are a class of compounds that have been shown toexert antiviral and anticancer activity both in vitro and in vivo, andthus, have been the subject of widespread research for the treatment ofviral infections. Nucleoside analogs are usually therapeuticallyinactive compounds that are converted by host or viral enzymes to theirrespective active anti-metabolites, which, in turn, may inhibitpolymerases involved in viral or cell proliferation. The activationoccurs by a variety of mechanisms, such as the addition of one or morephosphate groups and, or in combination with, other metabolic processes.

SUMMARY

Some embodiments disclosed herein relate to a compound of Formula (I) ora pharmaceutically acceptable salt thereof.

Some embodiments disclosed herein relate to a method of amelioratingand/or treating a hepatitis C viral (HCV) infection that can includeadministering to a subject identified as suffering from the HCVinfection an effective amount of one or more compounds of Formula (I),or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition that includes one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof. Other embodiments describedherein relate to using one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for ameliorating and/or treating a HCV infection. Still otherembodiments described herein relate to one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition that includes one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof, that can be used forameliorating and/or treating a HCV infection.

Some embodiments disclosed herein relate to a method of amelioratingand/or treating a HCV infection that can include contacting a cellinfected with the hepatitis C virus with an effective amount of one ormore compounds described herein, or a pharmaceutically acceptable saltof one or more compounds described herein, or a pharmaceuticalcomposition that includes one or more compounds described herein, or apharmaceutically acceptable salt thereof. Other embodiments describedherein relate to using one or more compounds described herein, or apharmaceutically acceptable salt of one or more compounds describedherein, in the manufacture of a medicament for ameliorating and/ortreating a HCV infection that can include contacting a cell infectedwith the hepatitis C virus with an effective amount of said compound(s).Still other embodiments described herein relate to one or more compoundsdescribed herein, or a pharmaceutically acceptable salt of one or morecompounds described herein, or a pharmaceutical composition thatincludes one or more compounds described herein, or a pharmaceuticallyacceptable salt thereof, that can be used for ameliorating and/ortreating a HCV infection by contacting a cell infected with thehepatitis C virus with an effective amount of said compound(s).

Some embodiments disclosed herein relate to a method of inhibitingreplication of a hepatitis C virus that can include contacting a cellinfected with the hepatitis C virus with an effective amount of one ormore compounds described herein, or a pharmaceutically acceptable saltof one or more compounds described herein, or a pharmaceuticalcomposition that includes one or more compounds described herein, or apharmaceutically acceptable salt thereof. Other embodiments describedherein relate to using one or more compounds described herein, or apharmaceutically acceptable salt of one or more compounds describedherein, in the manufacture of a medicament for inhibiting replication ofa hepatitis C virus that can include contacting a cell infected with thehepatitis C virus with an effective amount of said compound(s). Stillother embodiments described herein relate to one or more compoundsdescribed herein, or a pharmaceutically acceptable salt of one or morecompounds described herein, or a pharmaceutical composition thatincludes one or more compounds described herein, or a pharmaceuticallyacceptable salt thereof, that can be used for inhibiting replication ofa hepatitis C virus by contacting a cell infected with the hepatitis Cvirus with an effective amount of said compound(s).

Some embodiments disclosed herein relate to a method of amelioratingand/or treating a HCV infection that can include administering to asubject identified as suffering from the HCV infection an effectiveamount of a compound described herein or a pharmaceutically acceptablesalt thereof (for example, one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof), or a pharmaceuticalcomposition that includes a compound described herein, or apharmaceutically acceptable salt thereof, in combination with an agentselected from an interferon, ribavirin, a HCV protease inhibitor, a HCVpolymerase inhibitor, a NS5A inhibitor, an other antiviral compound, acompound of Formula (AA), a compound of Formula (BB) and a compound ofFormula (CC), or a pharmaceutically acceptable salt of any of theforegoing. Some embodiments disclosed herein relate to a method ofameliorating and/or treating a HCV infection that can include contactinga cell infected with the HCV infection with an effective amount of acompound described herein or a pharmaceutically acceptable salt thereof(for example, one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof), or a pharmaceuticalcomposition that includes a compound described herein, in combinationwith an agent selected from an interferon, ribavirin, a HCV proteaseinhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an otherantiviral compound, a compound of Formula (AA), a compound of Formula(BB) and a compound of Formula (CC), or a pharmaceutically acceptablesalt of any of the foregoing. Some embodiments disclosed herein relateto a method of inhibiting replication of a hepatitis C virus that caninclude administering to a subject identified as suffering from a HCVinfection an effective amount of a compound described herein or apharmaceutically acceptable salt thereof (for example, a compound ofFormula (I), or a pharmaceutically acceptable salt thereof), or apharmaceutical composition that includes a compound described herein, ora pharmaceutically acceptable salt thereof, in combination with an agentselected from an interferon, ribavirin, a HCV protease inhibitor, a HCVpolymerase inhibitor, a NS5A inhibitor, another antiviral compound, acompound of Formula (AA), a compound of Formula (BB) and a compound ofFormula (CC), or a pharmaceutically acceptable salt of any of theforegoing. In some embodiments, the agent can be a compound, or apharmaceutically acceptable salt thereof, selected from Compound1001-1016, 2001-2012, 3001-3014, 4001-4012, 5001-5012, 6001-6078,7000-7027 and 8000-8016, or a pharmaceutical composition that includesone or more of the aforementioned compounds, or a pharmaceuticallyacceptable salt of the foregoing. In some embodiments, the method caninclude administering a second agent selected from an interferon,ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5Ainhibitor, an other antiviral compound, a compound of Formula (AA), acompound of Formula (BB) and a compound of Formula (CC), or apharmaceutically acceptable salt of any of the foregoing.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows example HCV protease inhibitors.

FIG. 2 shows example nucleoside HCV polymerase inhibitors.

FIG. 3 shows example non-nucleoside HCV polymerase inhibitors.

FIG. 4 shows example NS5A inhibitors.

FIG. 5 shows example other antivirals.

FIG. 6 shows example compounds of Formula (CC) andalpha-thiotriphosphates thereof, wherein Formula (CC) andalpha-thiotriphosphates thereof are described herein.

FIG. 7 shows example compounds of Formula (AA), wherein Formula (AA) isdescribed herein.

FIG. 8 shows example compounds of Formula (BB), wherein Formula (BB) isdescribed herein.

FIG. 9 shows example compounds of Formula (I), wherein Formula (I) isdescribed herein.

FIG. 10 shows the gels from the assessment of incorporation of severalcompound with a uracil base by the human mitochondrial RNA polymerase.

FIG. 11 shows the gels from the assessment of incorporation of severalcompounds with a guanine base by the human mitochondrial RNA polymerase.

FIGS. 12A-D shows the results of the inhibition of mitochondrial proteinsynthesis assays.

DETAILED DESCRIPTION

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety unless stated otherwise. In the event that there are aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise.

As used herein, any “R” group(s) such as, without limitation, R¹, R²,R³, R⁴, R^(5A), R^(5B), R^(6A), R^(6B), R^(6C), R^(6D), R^(6E), R^(6F),R^(6G), R^(6H), R^(7A), R^(7B), R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵,R¹⁶, R¹⁷, R¹⁸, R^(A1), R^(A2), R^(A3) and R^(A4) represent substituentsthat can be attached to the indicated atom. An R group may besubstituted or unsubstituted. If two “R” groups are described as being“taken together” the R groups and the atoms they are attached to canform a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle. Forexample, without limitation, if R^(a) and R^(b) of an NR^(a)R^(b) groupare indicated to be “taken together,” it means that they are covalentlybonded to one another to form a ring:

In addition, if two “R” groups are described as being “taken together”with the atom(s) to which they are attached to form a ring as analternative, the R groups are not limited to the variables orsubstituents defined previously.

Whenever a group is described as being “optionally substituted” thatgroup may be unsubstituted or substituted with one or more of theindicated substituents. Likewise, when a group is described as being“unsubstituted or substituted” if substituted, the substituent(s) may beselected from one or more the indicated substituents. If no substituentsare indicated, it is meant that the indicated “optionally substituted”or “substituted” group may be substituted with one or more group(s)individually and independently selected from alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano,halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro,silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy,trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, amono-substituted amino group and a di-substituted amino group.

As used herein, “C_(a) to C_(b)” in which “a” and “b” are integers referto the number of carbon atoms in an alkyl, alkenyl or alkynyl group, orthe number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl,aryl, heteroaryl or heterocyclyl group. That is, the alkyl, alkenyl,alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of thearyl, ring of the heteroaryl or ring of the heterocyclyl can containfrom “a” to “b”, inclusive, carbon atoms. Thus, for example, a “C₁ to C₄alkyl” group refers to all alkyl groups having from 1 to 4 carbons, thatis, CH₃—, CH₃CH₂—, CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)—and (CH₃)₃C—. If no “a” and “b” are designated with regard to an alkyl,alkenyl, alkynyl, cycloalkyl cycloalkenyl, aryl, heteroaryl orheterocyclyl group, the broadest range described in these definitions isto be assumed.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that comprises a fully saturated (no double or triple bonds)hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms(whenever it appears herein, a numerical range such as “1 to 20” refersto each integer in the given range; e.g., “1 to 20 carbon atoms” meansthat the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 20 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 10 carbon atoms. The alkyl group could also be alower alkyl having 1 to 6 carbon atoms. The alkyl group of the compoundsmay be designated as “C₁-C₄ alkyl” or similar designations. By way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl chain, i.e., the alkyl chain is selected from methyl,ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl.Typical alkyl groups include, but are in no way limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl andhexyl. The alkyl group may be substituted or unsubstituted.

As used herein, “alkenyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more double bonds. Analkenyl group may be unsubstituted or substituted.

As used herein, “alkynyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more triple bonds. Analkynyl group may be unsubstituted or substituted.

As used herein, “cycloalkyl” refers to a completely saturated (no doubleor triple bonds) mono- or multi-cyclic hydrocarbon ring system. Whencomposed of two or more rings, the rings may be joined together in afused fashion. Cycloalkyl groups can contain 3 to 10 atoms in thering(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may beunsubstituted or substituted. Typical cycloalkyl groups include, but arein no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

As used herein, “cycloalkenyl” refers to a mono- or multi-cyclichydrocarbon ring system that contains one or more double bonds in atleast one ring; although, if there is more than one, the double bondscannot form a fully delocalized pi-electron system throughout all therings (otherwise the group would be “aryl,” as defined herein). Whencomposed of two or more rings, the rings may be connected together in afused fashion. A cycloalkenyl can contain 3 to 10 atoms in the ring(s)or 3 to 8 atoms in the ring(s). A cycloalkenyl group may beunsubstituted or substituted.

As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclicor multicyclic aromatic ring system (including fused ring systems wheretwo carbocyclic rings share a chemical bond) that has a fullydelocalized pi-electron system throughout all the rings. The number ofcarbon atoms in an aryl group can vary. For example, the aryl group canbe a C₆-C₁₄ aryl group, a C₆-C₁₀ aryl group, or a C₆ aryl group.Examples of aryl groups include, but are not limited to, benzene,naphthalene and azulene. An aryl group may be substituted orunsubstituted.

As used herein, “heteroaryl” refers to a monocyclic, bicyclic andtricyclic aromatic ring system (a ring system with fully delocalizedpi-electron system) that contain(s) one or more heteroatoms (forexample, 1 to 5 heteroatoms), that is, an element other than carbon,including but not limited to, nitrogen, oxygen and sulfur. The number ofatoms in the ring(s) of a heteroaryl group can vary. For example, theheteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atomsin the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term“heteroaryl” includes fused ring systems where two rings, such as atleast one aryl ring and at least one heteroaryl ring, or at least twoheteroaryl rings, share at least one chemical bond. Examples ofheteroaryl rings include, but are not limited to, furan, furazan,thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole,1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole,1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole,indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole,isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline,isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. Aheteroaryl group may be substituted or unsubstituted.

As used herein, “heterocyclyl” or “heteroalicyclyl” refers to three-,four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-memberedmonocyclic, bicyclic and tricyclic ring system wherein carbon atomstogether with from 1 to 5 heteroatoms constitute said ring system. Aheterocycle may optionally contain one or more unsaturated bondssituated in such a way, however, that a fully delocalized pi-electronsystem does not occur throughout all the rings. The heteroatom(s) is anelement other than carbon including, but not limited to, oxygen, sulfurand nitrogen. A heterocycle may further contain one or more carbonyl orthiocarbonyl functionalities, so as to make the definition includeoxo-systems and thio-systems such as lactams, lactones, cyclic imides,cyclic thioimides and cyclic carbamates. When composed of two or morerings, the rings may be joined together in a fused fashion.Additionally, any nitrogens in a heteroalicyclic may be quaternized.Heterocyclyl or heteroalicyclic groups may be unsubstituted orsubstituted. Examples of such “heterocyclyl” or “heteroalicyclyl” groupsinclude but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane,1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane,1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane,1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide,succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine,hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine,imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline,oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine,oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine,pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine,2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran,thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone andtheir benzo-fused analogs (e.g., benzimidazolidinone,tetrahydroquinoline and 3,4-methylenedioxyphenyl).

As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl groupconnected, as a substituent, via a lower alkylene group. The loweralkylene and aryl group of an aryl(alkyl) may be substituted orunsubstituted. Examples include but are not limited to benzyl,2-phenylalkyl, 3-phenylalkyl and naphthylalkyl.

As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to aheteroaryl group connected, as a substituent, via a lower alkylenegroup. The lower alkylene and heteroaryl group of heteroaralkyl may besubstituted or unsubstituted. Examples include but are not limited to2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl,pyridylalkyl, isoxazolylalkyl, imidazolylalkyl and their benzo-fusedanalogs.

A “(heteroalicyclyl)alkyl” and “(heterocyclyl)alkyl” refer to aheterocyclic or a heteroalicyclylic group connected, as a substituent,via a lower alkylene group. The lower alkylene and heterocyclyl of a(heteroalicyclyl)alkyl may be substituted or unsubstituted. Examplesinclude but are not limited tetrahydro-2H-pyran-4-yl)methyl,(piperidin-4-yl)ethyl, (piperidin-4-yl)propyl,(tetrahydro-2H-thiopyran-4-yl)methyl and (1,3-thiazinan-4-yl)methyl.

“Lower alkylene groups” are straight-chained —CH₂— tethering groups,forming bonds to connect molecular fragments via their terminal carbonatoms. Examples include but are not limited to methylene (—CH₂—),ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—) and butylene(—CH₂CH₂CH₂CH₂—). A lower alkylene group can be substituted by replacingone or more hydrogen of the lower alkylene group with a substituent(s)listed under the definition of “substituted.”

As used herein, “alkoxy” refers to the formula —OR wherein R is analkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl,heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or(heterocyclyl)alkyl is defined herein. A non-limiting list of alkoxysare methoxy, ethoxy, n-propoxy, 1-methylethoxy(isopropoxy), n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy maybe substituted or unsubstituted.

As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, oraryl connected, as substituents, via a carbonyl group. Examples includeformyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substitutedor unsubstituted.

As used herein, “hydroxyalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a hydroxy group. Exemplaryhydroxyalkyl groups include but are not limited to, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxypropyl and 2,2-dihydroxyethyl. A hydroxyalkylmay be substituted or unsubstituted.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkyl, di-haloalkyl and tri-haloalkyl). Such groups include butare not limited to, chloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 1-chloro-2-fluoromethyl and 2-fluoroisobutyl. Ahaloalkyl may be substituted or unsubstituted.

As used herein, “haloalkoxy” refers to an —O-alkyl group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). Such groups includebut are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. Ahaloalkoxy may be substituted or unsubstituted.

A “sulfenyl” group refers to an “—SR” group in which R can be hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl. Asulfenyl may be substituted or unsubstituted.

A “sulfinyl” group refers to an “—S(═O)—R” group in which R can be thesame as defined with respect to sulfenyl. A sulfinyl may be substitutedor unsubstituted.

A “sulfonyl” group refers to an “SO₂R” group in which R can be the sameas defined with respect to sulfenyl. A sulfonyl may be substituted orunsubstituted.

An “O-carboxy” group refers to a “RC(═O)O—” group in which R can behydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or(heterocyclyl)alkyl, as defined herein. An O-carboxy may be substitutedor unsubstituted.

The terms “ester” and “C-carboxy” refer to a “—C(═O)OR” group in which Rcan be the same as defined with respect to O-carboxy. An ester andC-carboxy may be substituted or unsubstituted.

A “thiocarbonyl” group refers to a “—C(═S)R” group in which R can be thesame as defined with respect to O-carboxy. A thiocarbonyl may besubstituted or unsubstituted.

A “trihalomethanesulfonyl” group refers to an “X₃CSO₂—” group whereineach X is a halogen.

A “trihalomethanesulfonamido” group refers to an “X₃CS(O)₂N(R_(A))—”group wherein each X is a halogen, and R_(A) is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl.

The term “amino” as used herein refers to a —NH₂ group.

As used herein, the term “hydroxy” refers to a —OH group.

A “cyano” group refers to a “—CN” group.

The term “azido” as used herein refers to a —N₃ group.

An “isocyanato” group refers to a “—NCO” group.

A “thiocyanato” group refers to a “—CNS” group.

An “isothiocyanato” group refers to an “—NCS” group.

A “mercapto” group refers to an “—SH” group.

A “carbonyl” group refers to a C═O group.

An “S-sulfonamido” group refers to a “—SO₂N(R_(A)R_(B))” group in whichR_(A) and R_(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),(heteroaryl)alkyl or (heterocyclyl)alkyl. An S-sulfonamido may besubstituted or unsubstituted.

An “N-sulfonamido” group refers to a “RSO₂N(R_(A))—” group in which Rand R_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),(heteroaryl)alkyl or (heterocyclyl)alkyl. An N-sulfonamido may besubstituted or unsubstituted.

An “O-carbamyl” group refers to a “—OC(═O)N(R_(A)R_(B))” group in whichR_(A) and R_(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),(heteroaryl)alkyl or (heterocyclyl)alkyl. An 0-carbamyl may besubstituted or unsubstituted.

An “N-carbamyl” group refers to an “ROC(═O)N(R_(A))—” group in which Rand R_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),(heteroaryl)alkyl or (heterocyclyl)alkyl. An N-carbamyl may besubstituted or unsubstituted.

An “O-thiocarbamyl” group refers to a “—OC(═S)—N(R_(A)R_(B))” group inwhich R_(A) and R_(B) can be independently hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl,aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl. An O-thiocarbamylmay be substituted or unsubstituted.

An “N-thiocarbamyl” group refers to an “ROC(═S)N(R_(A))—” group in whichR and R_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),(heteroaryl)alkyl or (heterocyclyl)alkyl. An N-thiocarbamyl may besubstituted or unsubstituted.

A “C-amido” group refers to a “—C(═O)N(R_(A)R_(B))” group in which R_(A)and R_(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),(heteroaryl)alkyl or (heterocyclyl)alkyl. A C-amido may be substitutedor unsubstituted.

An “N-amido” group refers to a “RC(═O)N(R_(A))—” group in which R andR_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),(heteroaryl)alkyl or (heterocyclyl)alkyl. An N-amido may be substitutedor unsubstituted.

The term “halogen atom” or “halogen” as used herein, means any one ofthe radio-stable atoms of column 7 of the Periodic Table of theElements, such as, fluorine, chlorine, bromine and iodine.

Where the numbers of substituents is not specified (e.g. haloalkyl),there may be one or more substituents present. For example “haloalkyl”may include one or more of the same or different halogens. As anotherexample, “C₁-C₃ alkoxyphenyl” may include one or more of the same ordifferent alkoxy groups containing one, two or three atoms.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (See, Biochem. 11:942-944(1972)).

The term “nucleoside” is used herein in its ordinary sense as understoodby those skilled in the art, and refers to a compound composed of anoptionally substituted pentose moiety or modified pentose moietyattached to a heterocyclic base or tautomer thereof via a N-glycosidicbond, such as attached via the 9-position of a purine-base or the1-position of a pyrimidine-base. Examples include, but are not limitedto, a ribonucleoside comprising a ribose moiety and adeoxyribonucleoside comprising a deoxyribose moiety. A modified pentosemoiety is a pentose moiety in which an oxygen atom has been replacedwith a carbon and/or a carbon has been replaced with a sulfur or anoxygen atom. A “nucleoside” is a monomer that can have a substitutedbase and/or sugar moiety. Additionally, a nucleoside can be incorporatedinto larger DNA and/or RNA polymers and oligomers. In some instances,the nucleoside can be a nucleoside analog drug.

The term “nucleotide” is used herein in its ordinary sense as understoodby those skilled in the art, and refers to a nucleoside having aphosphate ester bound to the pentose moiety, for example, at the5′-position.

As used herein, the term “heterocyclic base” refers to an optionallysubstituted nitrogen-containing heterocyclyl that can be attached to anoptionally substituted pentose moiety or modified pentose moiety. Insome embodiments, the heterocyclic base can be selected from anoptionally substituted purine-base, an optionally substitutedpyrimidine-base and an optionally substituted triazole-base (forexample, a 1,2,4-triazole). The term “purine-base” is used herein in itsordinary sense as understood by those skilled in the art, and includesits tautomers. Similarly, the term “pyrimidine-base” is used herein inits ordinary sense as understood by those skilled in the art, andincludes its tautomers. A non-limiting list of optionally substitutedpurine-bases includes purine, adenine, guanine, hypoxanthine, xanthine,alloxanthine, 7-alkylguanine (e.g. 7-methylguanine), theobromine,caffeine, uric acid and isoguanine. Examples of pyrimidine-basesinclude, but are not limited to, cytosine, thymine, uracil,5,6-dihydrouracil and 5-alkylcytosine (e.g., 5-methylcytosine). Anexample of an optionally substituted triazole-base is1,2,4-triazole-3-carboxamide. Other non-limiting examples ofheterocyclic bases include diaminopurine, 8-oxo-N⁶-alkyladenine (e.g.,8-oxo-N⁶-methyladenine), 7-deazaxanthine, 7-deazaguanine,7-deazaadenine, N⁴,N⁴-ethanocytosin, N⁶,N⁶-ethano-2,6-diaminopurine,5-halouracil (e.g., 5-fluorouracil and 5-bromouracil),pseudoisocytosine, isocytosine, isoguanine, and other heterocyclic basesdescribed in U.S. Pat. Nos. 5,432,272 and 7,125,855, which areincorporated herein by reference for the limited purpose of disclosingadditional heterocyclic bases. In some embodiments, a heterocyclic basecan be optionally substituted with an amine or an enol protectinggroup(s).

The term “—N-linked amino acid” refers to an amino acid that is attachedto the indicated moiety via a main-chain amino or mono-substituted aminogroup. When the amino acid is attached in an —N-linked amino acid, oneof the hydrogens that is part of the main-chain amino ormono-substituted amino group is not present and the amino acid isattached via the nitrogen. N-linked amino acids can be substituted orunsubstituted.

The term “—N-linked amino acid ester derivative” refers to an amino acidin which a main-chain carboxylic acid group has been converted to anester group. In some embodiments, the ester group has a formula selectedfrom alkyl-O—C(═O)—, cycloalkyl-O—C(═O)—, aryl-O—C(═O)— andaryl(alkyl)-O—C(═O)—. A non-limiting list of ester groups includesubstituted and unsubstituted versions of the following:methyl-O—C(═O)—, ethyl-O—C(═O)—, n-propyl-O—C(═O)—, isopropyl-O—C(═O)—,n-butyl-O—C(═O)—, isobutyl-O—C(═O)—, tert-butyl-O—C(═O)—,neopentyl-O—C(═O)—, cyclopropyl-O—C(═O)—, cyclobutyl-O—C(═O)—,cyclopentyl-0-C(═O)—, cyclohexyl-O—C(═O)—, phenyl-O—C(═O)—,benzyl-O—C(═O)— and naphthyl-O—C(═O)—. N-linked amino acid esterderivatives can be substituted or unsubstituted.

The term “—O-linked amino acid” refers to an amino acid that is attachedto the indicated moiety via the hydroxy from its main-chain carboxylicacid group. When the amino acid is attached in an —O-linked amino acid,the hydrogen that is part of the hydroxy from its main-chain carboxylicacid group is not present and the amino acid is attached via the oxygen.O-linked amino acids can be substituted or unsubstituted.

As used herein, the term “amino acid” refers to any amino acid (bothstandard and non-standard amino acids), including, but not limited to,α-amino acids, β-amino acids, γ-amino acids and δ-amino acids. Examplesof suitable amino acids include, but are not limited to, alanine,asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline,serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, threonine, tryptophan and valine. Additionalexamples of suitable amino acids include, but are not limited to,ornithine, hypusine, 2-aminoisobutyric acid, dehydroalanine,gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine,alpha-propyl-glycine and norleucine.

The terms “phosphorothioate” and “phosphothioate” refer to a compound ofthe general formula

its protonated forms (for example,

and its tautomers (such as

As used herein, the term “phosphate” is used in its ordinary sense asunderstood by those skilled in the art, and includes its protonatedforms (for example,

As used herein, the terms “monophosphate,” “diphosphate,” and“triphosphate” are used in their ordinary sense as understood by thoseskilled in the art, and include protonated forms.

The terms “protecting group” and “protecting groups” as used hereinrefer to any atom or group of atoms that is added to a molecule in orderto prevent existing groups in the molecule from undergoing unwantedchemical reactions. Examples of protecting group moieties are describedin T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 3. Ed. John Wiley & Sons, 1999, and in J. F. W. McOmie,Protective Groups in Organic Chemistry Plenum Press, 1973, both of whichare hereby incorporated by reference for the limited purpose ofdisclosing suitable protecting groups. The protecting group moiety maybe chosen in such a way, that they are stable to certain reactionconditions and readily removed at a convenient stage using methodologyknown from the art. A non-limiting list of protecting groups includebenzyl; substituted benzyl; alkylcarbonyls and alkoxycarbonyls (e.g.,t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls andarylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether(e.g. methoxymethyl ether); substituted ethyl ether; a substitutedbenzyl ether; tetrahydropyranyl ether; silyls (e.g., trimethylsilyl,triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl,tri-iso-propylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl ort-butyldiphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g.methoxymethylcarbonate); sulfonates (e.g. tosylate or mesylate); acyclicketal (e.g. dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane,1,3-dioxolanes and those described herein); acyclic acetal; cyclicacetal (e.g., those described herein); acyclic hemiacetal; cyclichemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or 1,3-dithiolane);orthoesters (e.g., those described herein) and triarylmethyl groups(e.g., trityl; monomethoxytrityl (MMTr); 4,4′-dimethoxytrityl (DMTr);4,4′,4″-trimethoxytrityl (TMTr); and those described herein).

The term “pharmaceutically acceptable salt” refers to a salt of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, the salt is an acidaddition salt of the compound. Pharmaceutical salts can be obtained byreacting a compound with inorganic acids such as hydrohalic acid (e.g.,hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid andphosphoric acid. Pharmaceutical salts can also be obtained by reacting acompound with an organic acid such as aliphatic or aromatic carboxylicor sulfonic acids, for example formic, acetic, succinic, lactic, malic,tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic,p-toluenesulfonic, salicylic or naphthalenesulfonic acid. Pharmaceuticalsalts can also be obtained by reacting a compound with a base to form asalt such as an ammonium salt, an alkali metal salt, such as a sodium ora potassium salt, an alkaline earth metal salt, such as a calcium or amagnesium salt, a salt of organic bases such as dicyclohexylamine,N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C₁-C₇ alkylamine,cyclohexylamine, triethanolamine, ethylenediamine, and salts with aminoacids such as arginine and lysine.

Terms and phrases used in this application, and variations thereof,especially in the appended claims, unless otherwise expressly stated,should be construed as open ended as opposed to limiting. As examples ofthe foregoing, the term ‘including’ should be read to mean ‘including,without limitation,’ ‘including but not limited to,’ or the like; theterm ‘comprising’ as used herein is synonymous with ‘including,’‘containing,’ or ‘characterized by,’ and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps; theterm ‘having’ should be interpreted as ‘having at least;’ the term‘includes’ should be interpreted as ‘includes but is not limited to;’the term ‘example’ is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof; and use of termslike ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words ofsimilar meaning should not be understood as implying that certainfeatures are critical, essential, or even important to the structure orfunction, but instead as merely intended to highlight alternative oradditional features that may or may not be utilized in a particularembodiment. In addition, the term “comprising” is to be interpretedsynonymously with the phrases “having at least” or “including at least”.When used in the context of a process, the term “comprising” means thatthe process includes at least the recited steps, but may includeadditional steps. When used in the context of a compound, composition ordevice, the term “comprising” means that the compound, composition ordevice includes at least the recited features or components, but mayalso include additional features or components. Likewise, a group ofitems linked with the conjunction ‘and’ should not be read as requiringthat each and every one of those items be present in the grouping, butrather should be read as ‘and/or’ unless expressly stated otherwise.Similarly, a group of items linked with the conjunction ‘or’ should notbe read as requiring mutual exclusivity among that group, but rathershould be read as ‘and/or’ unless expressly stated otherwise.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity. The indefinite article “a” or “an” does not exclude aplurality. A single processor or other unit may fulfill the functions ofseveral items recited in the claims. The mere fact that certain measuresare recited in mutually different dependent claims does not indicatethat a combination of these measures cannot be used to advantage. Anyreference signs in the claims should not be construed as limiting thescope.

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, enantiomerically enriched, racemicmixture, diastereomerically pure, diastereomerically enriched, or astereoisomeric mixture. In addition it is understood that, in anycompound described herein having one or more double bond(s) generatinggeometrical isomers that can be defined as E or Z, each double bond mayindependently be E or Z a mixture thereof.

Likewise, it is understood that, in any compound described, alltautomeric forms are also intended to be included. For example alltautomers of a phosphate and a phosphorothioate groups are intended tobe included. Examples of tautomers of a phosphorothioate include thefollowing:

Furthermore, all tautomers of heterocyclic bases known in the art areintended to be included, including tautomers of natural and non-naturalpurine-bases and pyrimidine-bases.

It is to be understood that where compounds disclosed herein haveunfilled valencies, then the valencies are to be filled with hydrogensor isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2(deuterium).

It is understood that the compounds described herein can be labeledisotopically. Substitution with isotopes such as deuterium may affordcertain therapeutic advantages resulting from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements. Each chemical element as represented in a compoundstructure may include any isotope of said element. For example, in acompound structure a hydrogen atom may be explicitly disclosed orunderstood to be present in the compound. At any position of thecompound that a hydrogen atom may be present, the hydrogen atom can beany isotope of hydrogen, including but not limited to hydrogen-1(protium) and hydrogen-2 (deuterium). Thus, reference herein to acompound encompasses all potential isotopic forms unless the contextclearly dictates otherwise.

It is understood that the methods and combinations described hereininclude crystalline forms (also known as polymorphs, which include thedifferent crystal packing arrangements of the same elemental compositionof a compound), amorphous phases, salts, solvates and hydrates. In someembodiments, the compounds described herein exist in solvated forms withpharmaceutically acceptable solvents such as water, ethanol, or thelike. In other embodiments, the compounds described herein exist inunsolvated form. Solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and may be formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, or the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Where a range of values is provided, it is understood that the upper andlower limit, and each intervening value between the upper and lowerlimit of the range is encompassed within the embodiments.

Compounds

Some embodiments disclosed herein relate to a compound of Formula (I) ora pharmaceutically acceptable salt thereof:

wherein: B¹ can be selected from an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

and an optionally substituted

R¹ can be selected from an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₂₋₆ alkenyl, an optionally substituted C₂₋₆alkynyl and an optionally substituted C₃₋₆ cycloalkyl; each-------- canbe absent or a single bond, provided that both -------- are each absentor both -------- are each a single bond; when both ------ are each asingle bond, then R² can be halo, N₃, —OR^(7A) or —N(R^(7B)R^(7C)); R⁴can be absent; R³ can be oxygen (O); and R^(p) can be

wherein Z^(p) can be oxygen (O) or sulfur (S) and R^(p1) can be selectedfrom O⁻, OH, an —O-optionally substituted C₁₋₆ alkyl

an optionally substituted N-linked amino acid and an optionallysubstituted N-linked amino acid ester derivative; when both ------ areeach absent, then R^(p) can be absent; R² can be halo, N₃, —OR^(7A) or—N(R^(7B)R^(7C)); R³ can be —OH or —OC(═O)R⁸; or R² and R³ can be eachan oxygen atom which are linked together by a carbonyl group; and R⁴ canbe hydrogen or

R^(5A) can be selected from O⁻, OH, an optionally substituted N-linkedamino acid, an optionally substituted N-linked amino acid esterderivative,

R^(5B) can be selected from O⁻, OH, an —O-optionally substituted aryl,an —O-optionally substituted heteroaryl, an —O-optionally substitutedheterocyclyl, an optionally substituted N-linked amino acid, anoptionally substituted N-linked amino acid ester derivative,

R^(6A) can be an optionally substituted C₁₋₆ alkyl or an optionallysubstituted C₃₋₆ cycloalkyl; R^(6B) and R⁶ can be independently selectedfrom hydrogen, an unsubstituted C₁₋₆ alkyl, an unsubstituted C₃₋₆alkenyl, an unsubstituted C₃₋₆ alkynyl and an unsubstituted C₃₋₆cycloalkyl; R^(6D) can be NHR^(6G); R^(6E) can be hydrogen, halogen orNHR^(6H); R^(6F) can be NHR^(6I); R^(6G) can be selected from hydrogen,an optionally substituted C₁₋₆ alkyl, an optionally substituted C₃₋₆alkenyl, an optionally substituted C₃₋₆ cycloalkyl, —C(═O)R^(A1) and—C(═O)OR^(A2); R^(6H) can be selected from hydrogen, an optionallysubstituted C₁₋₆ alkyl, an optionally substituted C₃₋₆ alkenyl, anoptionally substituted C₃₋₆ cycloalkyl, —C(═O)R^(A3) and —C(═O)OR^(A4);R^(6I) can be selected from hydrogen, an optionally substituted C₁₋₆alkyl, an optionally substituted C₃₋₆ alkenyl, an optionally substitutedC₃₋₆ cycloalkyl, —C(═O)R^(A5) and —C(═O)OR^(A6); X¹ can be N (nitrogen)or —CR^(6J), R^(6J) can be selected from hydrogen, halogen, anoptionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆alkenyl and an optionally substituted C₂₋₆ alkynyl; R^(A1), R^(A2),R^(A3), R^(A4), R^(A5) and R^(A6) can be independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkenyl, C₆₋₁₀ aryl, heteroaryl, heterocyclyl, aryl(C₁₋₆ alkyl),heteroaryl(C₁₋₆ alkyl) and heterocyclyl(C₁₋₆ alkyl); R^(7A) can behydrogen or —C(═O)R¹²; R^(7B) and R^(7C) can be independently hydrogenor an optionally substituted C₁₋₆ alkyl; R⁸ and R¹² can be independentlyan optionally substituted C₁₋₆ alkyl or an optionally substituted C₃₋₆cycloalkyl; R⁹, R¹⁰ and R¹¹ can be independently absent or hydrogen;R^(8A), R^(9A), R^(11A), R^(12A), R^(8B), R^(9B), R^(11B), R^(12B),R^(p2), R^(p3), R^(p5) and R^(p6) can be independently selected fromhydrogen, an optionally substituted C₁₋₂₄ alkyl and an optionallysubstituted aryl; R^(10A), R^(10B), R^(13A), R^(13B), R^(p4) and R^(p7)can be independently selected from hydrogen, an optionally substitutedC₁₋₂₄ alkyl, an optionally substituted aryl, an optionally substituted—O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionallysubstituted —O-heteroaryl and an optionally substituted —O-monocyclicheterocyclyl; R^(14A), R^(14B), R^(15A), R^(15B), R^(p8) and R^(p9) canbe independently selected from hydrogen, an optionally substituted C₁₋₂₄alkyl and an optionally substituted aryl; n can be 0 or 1; p, q, and rcan be independently 1 or 2; s, t and u can be independently 3, 4 or 5;Z¹, Z^(1A), Z^(1B) and Z^(p1) can be independently O (oxygen) or S(sulfur); and provided that when R⁴ is

and R^(5A) is O⁻ or OH, then R^(5B) is O⁻, OH,

an optionally substituted N-linked amino acid or an optionallysubstituted N-linked amino acid ester derivative.

The substituents attached to the 2′-carbon can vary. In someembodiments, R² can be halo. For example, R² can be fluoro or chloro. Inother embodiments, R² can be N₃. In some embodiments, R² can be —OH. Inother embodiments, R² can be OR^(7A), wherein R^(7A) can be —C(═O)R¹²,and R¹² can be an optionally substituted C₁₋₆ alkyl. Suitable alkylgroups include, but are not limited to optionally substituted variantsof the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, pentyl (branched and straight-chained) and hexyl (branchedand straight-chained). In yet still other embodiments, R² can beOR^(7A), wherein R^(7A) can be —C(═O)R¹², and R¹² can be an optionallysubstituted C₃₋₆ cycloalkyl. Suitable cycloalkyl groups include, but arenot limited to optionally substituted variants of the following:cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiment,R² can be —N(R^(7B)R^(7C)), wherein R^(7B) and R^(7C) can beindependently hydrogen or an optionally substituted C₁₋₆ alkyl. In someembodiments, R^(7B) and R^(7C) can be both hydrogen, such that R² can be—NH₂. In other embodiments, at least one of R^(7B) and R^(7C) can be anoptionally substituted C₁₋₆ alkyl. In some embodiments, R^(7B) andR^(7C) can be both an optionally substituted C₁₋₆ alkyl. In someembodiments, R^(7B) and R^(7C) can be the same. In other embodiments,R^(7B) and R^(7C) can be different.

Various substituents can be attached to the 3′-carbon of the pentosering. In some embodiments, R³ can be —OH. In other embodiments, R³ canbe —OC(═O)R⁸, wherein R⁸ can be an optionally substituted C₁₋₆ alkylsuch as those described herein. In still other embodiments, R³ can be—OC(═O)R⁸, wherein R⁸ can be an optionally substituted C₃₋₆ cycloalkyl.Examples of suitable optionally substituted C₃₋₆ cycloalkyl groups aredescribed herein.

In some embodiments, R² and R³ can each be an oxygen atom and the oxygenatoms can be linked together by a carbonyl group. In other embodiments,R² and R³ can be both —OH. In other embodiments, R² can be halo and R³can be —OH. In still other embodiments, R² can be halo and R³ can be—OC(═O)R⁸.

In some embodiments, R¹ can be an optionally substituted C₁₋₆ alkyl. Insome embodiments, R¹ can be an unsubstituted C₁₋₆ alkyl. For example, R¹can be unsubstituted methyl, unsubstituted ethyl, unsubstitutedn-propyl, unsubstituted isopropyl, unsubstituted n-butyl, unsubstitutedisobutyl, unsubstituted tert-butyl, unsubstituted pentyl (branched andstraight-chained) or unsubstituted hexyl (branched andstraight-chained). In some embodiments, R¹ can be a substituted C₁₋₆alkyl. Suitable substitutions are described herein. As an example, R¹can be a halo-substituted C₁₋₆ alkyl (such as —CF₃ or —CH₂CH₂F). Inother embodiments, R¹ can be an optionally substituted C₂₋₆ alkenyl.Suitable alkenyl groups include, but are not limited to optionallysubstituted variants of the following: ethenyl, n-propenyl, isopropenyl,n-butenyl, isobutenyl, tert-butenyl, pentenyl (branched andstraight-chained), hexenyl (branched and straight-chained), vinyl andallenyl. In still other embodiments, R¹ can be an optionally substitutedC₂₋₆ alkynyl. In yet still other embodiments, R¹ can be an optionallysubstituted C₃₋₆ cycloalkyl, such as those described herein.

In some embodiments, both ------ can be each absent, R^(p) can beabsent; R² can be halo, N₃, —OR^(7A) or —N(R^(7B)R^(7C)); R³ can be —OHor —OC(═O)R⁸; or R² and R³ can be each an oxygen atom which are linkedtogether by a carbonyl group; and R⁴ can be hydrogen or

When both ------ are absent, Formula (I) can have the structure:

In some embodiments, R⁴ can be hydrogen. In other embodiments, R⁴ can be

In some embodiments, the compound of Formula (I) can be a monophosphate.In other embodiments, the compound of Formula (I) can be athiomonophosphate. In some embodiments, the compound of Formula (I) canbe a diphosphate. In other embodiments, the compound of Formula (I) canbe an alpha-thiodiphosphate. In some embodiments, the compound ofFormula (I) can be a triphosphate. In other embodiments, the compound ofFormula (I) can be an alpha-thiotriphosphate. In some embodiments, R⁴can be

R^(5A) can be O⁻ or OH; and R^(5B) can be O⁻ or OH. In otherembodiments, R⁴ can be

R^(5A) can be O⁻ or OH; R^(5B) can be

and n can be 0. In still other embodiments, R⁴ can be

R^(5A) can be O⁻ or OH; R^(5B) can be

and n can be 1. The substituents attached to the phosphorus can vary. Insome embodiments, a compound of Formula (I) can be a phosphoroamidate.In other embodiments, a compound of Formula (I) can be athiophosphoroamidate. In still other embodiments, a compound of Formula(I) can be a phosphorbisamidate. In yet still other embodiments, acompound of Formula (I) can be a thiophosphorbisamidate.

In some embodiments, R^(5A) can be an optionally substituted N-linkedamino acid. Various amino acids are suitable, including those describedherein. Examples of suitable amino acids include, but are not limitedto, alanine, asparagine, aspartate, cysteine, glutamate, glutamine,glycine, proline, serine, tyrosine, arginine, histidine, isoleucine,leucine, lysine, methionine, phenylalanine, threonine, tryptophan andvaline. In other embodiments, R^(5A) can be an optionally substitutedN-linked amino acid ester derivative. Examples of N-linked amino acidester derivatives include, but are not limited to, ester derivatives ofany of the following amino acids: alanine, asparagine, aspartate,cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine,arginine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, threonine, tryptophan and valine. Additional examples ofN-linked amino acid ester derivatives include, but are not limited to,an ester derivative of any of the following amino acids:alpha-ethyl-glycine, alpha-propyl-glycine and beta-alanine. In someembodiments, the N-linked amino acid ester derivative can be a C₁₋₆alkyl ester derivative, for example, an isopropyl ester of alanine. Inother embodiments, the N-linked amino acid ester derivative can be aC₃₋₆ cycloalkyl ester derivative, such as a cyclohexyl ester of alanine.

In some embodiments, R^(5A) can have the structure

wherein R¹³ can be selected from hydrogen, an optionally substitutedC₁₋₆-alkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₆ alkyl) and anoptionally substituted haloalkyl; R¹⁴ can be selected from hydrogen, anoptionally substituted C₁₋₆ alkyl, an optionally substituted C₁₋₆haloalkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted C₆ aryl, an optionally substituted C₁₀ aryl and anoptionally substituted aryl(C₁₋₆ alkyl); and R¹⁵ can be hydrogen or anoptionally substituted C₁₋₄-alkyl; or R¹⁴ and R¹⁵ can be taken togetherto form an optionally substituted C₃₋₆ cycloalkyl.

When R¹⁴ is substituted, R¹⁴ can be substituted with one or moresubstituents selected from N-amido, mercapto, alkylthio, an optionallysubstituted aryl, hydroxy, an optionally substituted heteroaryl,O-carboxy and amino. In some embodiments, R¹⁴ can be an unsubstitutedC₁₋₆-alkyl, such as those described herein. In some embodiments, R¹⁴ canbe hydrogen. In other embodiments, R¹⁴ can be methyl. In someembodiments, R¹³ can be an optionally substituted C₁₋₆ alkyl. Examplesof optionally substituted C₁₋₆-alkyls include optionally substitutedvariants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, pentyl (branched and straight-chained) and hexyl(branched and straight-chained). In some embodiments, le can be methylor isopropyl. In some embodiments, le can be ethyl or neopentyl. Inother embodiments, le can be an optionally substituted C₃₋₆ cycloalkyl.Examples of optionally substituted C₃₋₆ cycloalkyl include optionallysubstituted variants of the following: cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. In some embodiments, le can be an optionallysubstituted cyclohexyl. In still other embodiments, R¹³ can be anoptionally substituted aryl, such as phenyl and naphthyl. In yet stillother embodiments, le can be an optionally substituted aryl(C₁₋₆ alkyl).In some embodiments, R¹³ can be an optionally substituted benzyl. Insome embodiments, R¹³ can be an optionally substituted C₁₋₆ haloalkyl,for example, CF₃. In some embodiments, R¹⁵ can be hydrogen. In otherembodiments, R¹⁵ can be an optionally substituted C₁₋₄ alkyl, such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. Insome embodiments, R¹⁵ can be methyl. In some embodiments, R¹⁴ and R¹⁵can be taken together to form an optionally substituted C₃₋₆ cycloalkyl.Examples of optionally substituted C₃₋₆ cycloalkyl include optionallysubstituted variants of the following: cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. Depending on the groups that are selectedfor R¹⁴ and R¹⁵, the carbon to which R¹⁴ and R¹⁵ are attached may be achiral center. In some embodiment, the carbon to which R¹⁴ and R¹⁵ areattached may be a (R)-chiral center. In other embodiments, the carbon towhich R¹⁴ and R¹⁵ are attached may be a (S)-chiral center.

Examples of suitable

groups include the following:

In some embodiments, R^(5B) can be an —O-optionally substituted aryl.For example, R^(5B) can be an —O-optionally substituted phenyl. When thephenyl is substituted, the ring can be substituted 1, 2, 3 or more than3 times. Suitable mono-substituted phenyl groups include,ortho-substituted phenyl, meta-substituted phenyl and para-substitutedphenyl. In other embodiments, R^(5B) can be an —O-unsubstituted aryl.Alternatively, R^(5B) can be an —O-optionally substituted naphthyl. Inother embodiments, R^(5B) can be an —O-optionally substitutedheteroaryl. For example, R^(5B) can be an —O-optionally substitutedquinolinyl. In still other embodiments, R^(5B) can be an —O-optionallysubstituted heterocyclyl.

In some embodiments, R^(5B) is an optionally substituted N-linked aminoacid, such as those described for R^(5A). In other embodiments, R^(5B)is an optionally substituted N-linked amino acid ester derivative, forexample, those described herein. In some embodiments, R^(5B) can havethe structure

wherein R¹⁶ can be selected from hydrogen, an optionally substitutedC₁₋₆-alkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₆ alkyl) and anoptionally substituted haloalkyl; R¹⁷ can be selected from hydrogen, anoptionally substituted C₁₋₆ alkyl, an optionally substituted C₁₋₆haloalkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted C₆ aryl, an optionally substituted C₁₀ aryl and anoptionally substituted aryl(C₁₋₆ alkyl); and R¹⁸ can be hydrogen or anoptionally substituted C₁₋₄-alkyl; or R¹⁷ and R¹⁸ can be taken togetherto form an optionally substituted C₃₋₆ cycloalkyl.

When R¹⁷ is substituted, R¹⁷ can be substituted with one or moresubstituents selected from N-amido, mercapto, alkylthio, an optionallysubstituted aryl, hydroxy, an optionally substituted heteroaryl,O-carboxy and amino. In some embodiments, R¹⁷ can be an unsubstitutedC₁₋₆-alkyl, such as those described herein. In some embodiments, R¹⁷ canbe hydrogen. In other embodiments, R¹⁷ can be methyl. In someembodiments, R¹⁶ can be an optionally substituted C₁₋₆ alkyl. Examplesof optionally substituted C₁₋₆-alkyls include optionally substitutedvariants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, pentyl (branched and straight-chained) and hexyl(branched and straight-chained). In some embodiments, R¹⁶ can be methylor isopropyl. In some embodiments, R¹⁶ can be ethyl or neopentyl. Inother embodiments, R¹⁶ can be an optionally substituted C₃₋₆ cycloalkyl.Examples of optionally substituted C₃₋₆ cycloalkyl include optionallysubstituted variants of the following: cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. In some embodiments, R¹⁶ can be anoptionally substituted cyclohexyl. In still other embodiments, R¹⁶ canbe an optionally substituted aryl, such as phenyl and naphthyl. In yetstill other embodiments, R¹⁶ can be an optionally substituted aryl(C₁₋₆alkyl). In some embodiments, R¹⁶ can be an optionally substitutedbenzyl. In some embodiments, R¹⁶ can be an optionally substituted C₁₋₆haloalkyl, for example, CF₃. In some embodiments, R¹⁸ can be hydrogen.In other embodiments, R¹⁸ can be an optionally substituted C₁₋₄-alkyl,such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl ortert-butyl. In some embodiments, R¹⁸ can be methyl. In some embodiments,R¹⁷ and R¹⁸ can be taken together to form an optionally substituted C₃₋₆cycloalkyl. Examples of optionally substituted C₃₋₆ cycloalkyl includeoptionally substituted variants of the following: cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl. Depending on the groups that areselected for R¹⁷ and R¹⁸, the carbon to which R¹⁷ and R¹⁸ are attachedmay be a chiral center. In some embodiment, the carbon to which R¹⁷ andR¹⁸ are attached may be a (R)-chiral center. In other embodiments, thecarbon to which R¹⁷ and R¹⁸ are attached may be a (S)-chiral center.

Examples of suitable

groups include the following:

In some embodiments, R^(5A) can be an optionally substituted N-linkedamino acid or an optionally substituted N-linked amino acid esterderivative and R^(5B) can be an —O-optionally substituted aryl. In otherembodiments, R^(5A) can be an optionally substituted N-linked amino acidor an optionally substituted N-linked amino acid ester derivative andR^(5B) can be an —O-optionally substituted heteroaryl. In someembodiments, R^(5A) can be an optionally substituted N-linked amino acidor an optionally substituted N-linked amino acid ester derivative andR^(5A) can be an optionally substituted N-linked amino acid or anoptionally substituted N-linked amino acid ester derivative.

In some embodiments, R^(5A) can be

When R^(5A) is

R^(8A) and R^(9A) can be independently selected from hydrogen, anoptionally substituted C₁₋₂₄ alkyl and an optionally substituted aryl;and R^(10A) can be selected from hydrogen, an optionally substitutedC₁₋₂₄ alkyl, an optionally substituted aryl, an optionally substituted—O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionallysubstituted —O-heteroaryl and an optionally substituted —O-monocyclicheterocyclyl. In some embodiments, R^(8A) and R^(9A) can be hydrogen. Inother embodiments, at least one of R^(8A) and R^(9A) can be anoptionally substituted C₁₋₂₄ alkyl or an optionally substituted aryl. Insome embodiments, R^(10A) can be hydrogen. In other embodiments, R^(10A)can be an optionally substituted C₁₋₂₄ alkyl. In some embodiments,R^(10A) can be an unsubstituted C₁₋₄ alkyl. In still other embodiments,R^(10A) can be an optionally substituted aryl. In yet still otherembodiments, R^(10A) can be —O—C₁₋₂₄ alkyl, an optionally substituted—O-aryl, an optionally substituted —O-heteroaryl or an optionallysubstituted —O-monocyclic heterocyclyl. In some embodiments, R^(10A) canbe an unsubstituted —O—C₁₋₄ alkyl.

In some embodiments, R^(5B) can be

When R^(5B) is

R^(8B) and R^(9B) can be independently selected from hydrogen, anoptionally substituted C₁₋₂₄ alkyl and an optionally substituted aryl;and R^(10B) can be selected from hydrogen, an optionally substitutedC₁₋₂₄ alkyl, an optionally substituted aryl, an optionally substituted—O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionallysubstituted —O-heteroaryl and an optionally substituted —O-monocyclicheterocyclyl. In some embodiments, R^(8B) and R^(9B) can be hydrogen. Inother embodiments, at least one of R^(8B) and R^(9B) can be anoptionally substituted C₁₋₂₄ alkyl or an optionally substituted aryl. Insome embodiments, R^(10B) can be hydrogen. In other embodiments, R^(10B)can be an optionally substituted C₁₋₂₄ alkyl. In some embodiments,R^(10B) can be an unsubstituted C₁₋₄ alkyl. In still other embodiments,R^(10B) can be an optionally substituted aryl. In yet still otherembodiments, R^(10B) can be —O—C₁₋₂₄ alkyl, an optionally substituted—O-aryl, an optionally substituted —O-heteroaryl or an optionallysubstituted —O-monocyclic heterocyclyl. In some embodiments, R^(10B) canbe an unsubstituted —O—C₁₋₄ alkyl. In some embodiments, R^(5A) can be

and R^(5B) can be

In some embodiments, R^(5A) can be

wherein R^(11A) and R^(12A) can be independently selected from hydrogen,an optionally substituted C₁₋₂₄ alkyl and an optionally substitutedaryl; R^(13A) can be independently selected from hydrogen, an optionallysubstituted C₁₋₂₄ alkyl, an optionally substituted aryl, an optionallysubstituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, anoptionally substituted —O-heteroaryl and an optionally substituted—O-monocyclic heterocyclyl; and Z^(1A) can be independently O (oxygen)or S (sulfur). In some embodiments, R^(11A) and R^(12A) can be hydrogen.In other embodiments, at least one of R^(11A) and R^(12A) can be anoptionally substituted C₁₋₂₄ alkyl or an optionally substituted aryl. Insome embodiments, R^(13A) can be an optionally substituted C₁₋₂₄ alkyl.In some embodiments, R^(13A) can be an unsubstituted C₁₋₄ alkyl. Inother embodiments, R^(13A) can be an optionally substituted aryl. Instill other embodiments, R^(13A) can be an optionally substituted—O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionallysubstituted —O-heteroaryl or an optionally substituted —O-monocyclicheterocyclyl. In some embodiments, R^(13A) can be an unsubstituted—O—C₁₋₄ alkyl. In some embodiments, Z^(1A) can be O (oxygen). In otherembodiments, Z^(1A) can be or S (sulfur).

In some embodiments, R^(5B) can be

wherein R^(11B) and R^(12B) can be independently selected from hydrogen,an optionally substituted C₁₋₂₄ alkyl and an optionally substitutedaryl; R^(13B) can be independently selected from hydrogen, an optionallysubstituted C₁₋₂₄ alkyl, an optionally substituted aryl, an optionallysubstituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, anoptionally substituted —O-heteroaryl and an optionally substituted—O-monocyclic heterocyclyl; and Z^(1B) can be independently O (oxygen)or S (sulfur). In some embodiments, R^(11B) and R^(12B) can be hydrogen.In other embodiments, at least one of R^(11B) and R^(12B) can be anoptionally substituted C₁₋₂₄ alkyl or an optionally substituted aryl. Insome embodiments, R^(13B) can be an optionally substituted C₁₋₂₄ alkyl.In some embodiments, R^(13B) can be an unsubstituted C₁₋₄ alkyl. Inother embodiments, R^(13B) can be an optionally substituted aryl. Instill other embodiments, R^(13B) can be an optionally substituted—O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionallysubstituted —O-heteroaryl or an optionally substituted —O-monocyclicheterocyclyl. In some embodiments, R^(13B) can be an unsubstituted—O—C₁₋₄ alkyl. In some embodiments, Z^(1B) can be O (oxygen). In otherembodiments, Z^(1B) can be or S (sulfur). In some embodiments, R^(5A)can be

and R^(5B) can be

In some embodiments, R^(5A) can be

In some embodiments, R^(14A) can be hydrogen. In other embodiments,R^(14A) can be an optionally substituted C₁₋₂₄ alkyl. In still otherembodiments, R^(14A) can be an optionally substituted aryl. In someembodiments, R^(14A) can be a C₁₋₆ alkyl, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In someembodiments, p can be 1. In other embodiments, p can be 2.

In some embodiments, R^(5B) can be

In some embodiments, R^(14B) can be hydrogen. In other embodiments,R^(14B) can be an optionally substituted C₁₋₂₄ alkyl. In still otherembodiments, R^(14B) can be an optionally substituted aryl. In someembodiments, R^(14B) can be a C₁₋₆ alkyl, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In someembodiments, q can be 1. In other embodiments, q can be 2. In someembodiments, R^(5A) can be

and R^(5B) can be

In some embodiments, R^(5A) can be

In some embodiments, R^(15A) can be hydrogen. In other embodiments,R^(15A) can be an optionally substituted C₁₋₂₄ alkyl. In still otherembodiments, R^(15A) can be an optionally substituted aryl, for example,an optionally substituted phenyl. In some embodiments, R^(15A) can be anoptionally substituted C₁₋₆ alkyl. In some embodiments, R^(15A) can bean unsubstituted C₁₋₆ alkyl. In some embodiments, s can be 3. In otherembodiments, s can be 4. In still other embodiments, s can be 5.

In some embodiments, R^(5B) can be

In some embodiments, R^(15B) can be hydrogen. In other embodiments,R^(15B) can be an optionally substituted C₁₋₂₄ alkyl. In still otherembodiments, R^(15B) can be an optionally substituted aryl, for example,an optionally substituted phenyl. In some embodiments, R^(15B) can be anoptionally substituted C₁₋₆ alkyl. In some embodiments, R^(15B) can bean unsubstituted C₁₋₆ alkyl. In some embodiments, t can be 3. In otherembodiments, t can be 4. In still other embodiments, t can be 5. In someembodiments, R^(5A) can be

and R^(5B) can be

In some embodiments, R^(5A) and/or R^(5B) can beisopropyloxycarbonyloxymethoxy (POC) group. In some embodiments, R^(5A)and/or R^(5B) can be pivaloyloxymethoxy (POM) group. In someembodiments, R^(5A) and R^(5B) can be both aisopropyloxycarbonyloxymethoxy (POC) group, and form abis(isopropyloxycarbonyloxymethoxy) (bis(POC)) prodrug. In otherembodiments, R^(5A) and R^(5B) can be both a pivaloyloxymethoxy (POM)group, and form a bis(pivaloyloxymethoxy) (bis(POM)) prodrug. In stillother embodiments, R^(5A) and R^(5B) can be both a S-acylthioethyl(SATE)-O— group and form a SATE ester prodrug. In some embodiments,R^(5A) and R^(5B) can be the same. In other embodiments, R^(5A) andR^(5B) can be different.

In some embodiments, both -------- can be each a single bond; R⁴ can beabsent; R³ can be oxygen (O); and R^(p) can be

wherein Z^(p) can be oxygen (O) or sulfur (S) and R^(p1) can be selectedfrom O⁻, OH, an —O-optionally substituted C₁₋₆ alkyl.

an optionally substituted N-linked amino acid and an optionallysubstituted N-linked amino acid ester derivative. When both ------ areeach a single bond, Formula (I) can have the structure:

In some embodiments, R^(p1) can be O⁻. In other embodiments, R^(p1) canbe OH. In other embodiments, R^(p1) can be an —O-optionally substitutedC₁₋₆ alkyl. For example, R^(p1) can be a substituted or an unsubstitutedversion of the following: methoxy, ethoxy, n-propoxy, iso-propoxy,n-butoxy, iso-butoxy, tert-butoxy, pentoxy (branched or straightchained) and hexoxy (branched or straight chained).

In some embodiments, R^(p1) can be

wherein R^(p1) and R^(p3) can be independently selected from hydrogen,an optionally substituted C₁₋₂₄ alkyl and an optionally substitutedaryl; and R^(p4) can be selected from hydrogen, an optionallysubstituted C₁₋₂₄ alkyl, an optionally substituted aryl, an optionallysubstituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, anoptionally substituted —O-heteroaryl and an optionally substituted—O-monocyclic heterocyclyl. In some embodiments, R^(p1) and R^(p3) canbe hydrogen. In other embodiments, at least one of R^(p1) and R^(p3) canbe an optionally substituted C₁₋₂₄ alkyl or an optionally substitutedaryl. In some embodiments, R^(p4) can be an optionally substituted C₁₋₂₄alkyl. In some embodiments, R^(p4) can be an unsubstituted C₁₋₄ alkyl.In other embodiments, R^(p4) can be an optionally substituted aryl. Instill other embodiments, R^(p4) can be an optionally substituted—O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionallysubstituted —O-heteroaryl or an optionally substituted —O-monocyclicheterocyclyl. In some embodiments, R^(p4) can be an unsubstituted—O—C₁₋₄ alkyl.

In some embodiments, R^(p1) can be

wherein R^(p5) and R^(p6) can be independently selected from hydrogen,an optionally substituted C₁₋₂₄ alkyl and an optionally substitutedaryl; R^(p7) can be independently selected from hydrogen, an optionallysubstituted C₁₋₂₄ alkyl, an optionally substituted aryl, an optionallysubstituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, anoptionally substituted —O-heteroaryl and an optionally substituted—O-monocyclic heterocyclyl; and Z^(p1) can be independently O (oxygen)or S (sulfur). In some embodiments, R^(p5) and R^(p6) can be hydrogen.In other embodiments, at least one of R^(p5) and R^(p6) can be anoptionally substituted C₁₋₂₄ alkyl or an optionally substituted aryl. Insome embodiments, R^(p7) can be an optionally substituted C₁₋₂₄ alkyl.In some embodiments, R^(p7) can be an unsubstituted C₁₋₄ alkyl. In otherembodiments, R^(p7) can be an optionally substituted aryl. In stillother embodiments, R^(p7) can be an optionally substituted —O—C₁₋₂₄alkyl, an optionally substituted —O-aryl, an optionally substituted—O-heteroaryl or an optionally substituted —O-monocyclic heterocyclyl.In some embodiments, R^(p7) can be an unsubstituted —O—C₁₋₄ alkyl. Insome embodiments, Z^(p1) can be O (oxygen). In other embodiments, Z^(p1)can be or S (sulfur). In some embodiments, R^(p1) can beisopropyloxycarbonyloxymethyloxy (POC) group. In some embodiments,R^(p1) can be pivaloyloxymethyloxy (POM) group.

In some embodiments, R^(p1) can be

In some embodiments, R^(p8) can be hydrogen. In other embodiments,R^(p8) can be an optionally substituted C₁₋₂₄ alkyl. In still otherembodiments, R^(p8) can be an optionally substituted aryl. In someembodiments, R^(p8) can be a C₁₋₆ alkyl, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In someembodiments, r can be 1. In other embodiments, r can be 2.

In some embodiments, R^(p1) can be

In some embodiments, R^(p9) can be hydrogen. In other embodiments,R^(p9) can be an optionally substituted C₁₋₂₄ alkyl. In still otherembodiments, R^(p9) can be an optionally substituted aryl, for example,an optionally substituted phenyl. In some embodiments, R^(p9) can be anoptionally substituted C₁₋₆ alkyl. In some embodiments, R^(p9) can be anunsubstituted C₁₋₆ alkyl. In some embodiments, u can be 3. In otherembodiments, u can be 4. In still other embodiments, u can be 5. In someembodiments, R^(p1) can be a S-acylthioethyl (SATE) group and form aSATE ester prodrug.

In some embodiments, R^(p1) can be an optionally substituted N-linkedamino acid or an optionally substituted N-linked amino acid esterderivative. For example, R^(p1) can be optionally substituted version ofthe following: alanine, asparagine, aspartate, cysteine, glutamate,glutamine, glycine, proline, serine, tyrosine, arginine, histidine,isoleucine, leucine, lysine, methionine, phenylalanine, threonine,tryptophan, valine and ester derivatives thereof. In some embodiments,R^(p1) can be selected from N-alanine isopropyl ester, N-alaninecyclohexyl ester, N-alanine neopentyl ester, N-valine isopropyl esterand N-leucine isopropyl ester. In some embodiments, R^(p1) can have thestructure

wherein R^(p10) can be selected from hydrogen, an optionally substitutedC₁₋₆-alkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₆ alkyl) and anoptionally substituted haloalkyl; R^(p11) can be selected from hydrogen,an optionally substituted C₁₋₆ alkyl, an optionally substituted C₁₋₆haloalkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted C₆ aryl, an optionally substituted C₁₀ aryl and anoptionally substituted aryl(C₁₋₆ alkyl); and R^(p12) can be hydrogen oran optionally substituted C₁₋₄-alkyl; or R^(p11) and R^(p12) can betaken together to form an optionally substituted C₃₋₆ cycloalkyl.

When R^(p11) is substituted, R^(p11) can be substituted with one or moresubstituents selected from N-amido, mercapto, alkylthio, an optionallysubstituted aryl, hydroxy, an optionally substituted heteroaryl,O-carboxy, and amino. In some embodiments, R^(p11) can be anunsubstituted C₁₋₆-alkyl, such as those described herein. In someembodiments, R^(p11) can be hydrogen. In other embodiments, R^(p11) canbe methyl. In some embodiments, R^(p10) can be an optionally substitutedC₁₋₆ alkyl. Examples of optionally substituted C₁₋₆-alkyls includeoptionally substituted variants of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In someembodiments, R^(p10) can be methyl or isopropyl. In some embodiments,R^(p10) can be ethyl or neopentyl. In other embodiments, R^(p10) can bean optionally substituted C₃₋₆ cycloalkyl. Examples of optionallysubstituted C₃₋₆ cycloalkyl include optionally substituted variants ofthe following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Insome embodiments, R^(p10) can be an optionally substituted cyclohexyl.In still other embodiments, R^(p10) can be an optionally substitutedaryl, such as phenyl and naphthyl. In yet still other embodiments,R^(p10) can be an optionally substituted aryl(C₁₋₆ alkyl). In someembodiments, R^(p10) can be an optionally substituted benzyl. In someembodiments, R^(p10) can be an optionally substituted C₁₋₆ haloalkyl,for example, CF₃. In some embodiments, R^(p12) can be hydrogen. In otherembodiments, R^(p12) can be an optionally substituted C₁₋₄-alkyl, suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.In some embodiments, R^(p12) can be methyl. In some embodiments, R^(p11)and R^(p12) can be taken together to form an optionally substituted C₃₋₆cycloalkyl. Examples of optionally substituted C₃₋₆ cycloalkyl includeoptionally substituted variants of the following: cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl. Depending on the groups thatare selected for R^(p11) and R^(p12), the carbon to which R^(p11) andR^(p12) are attached may be a chiral center. In some embodiment, thecarbon to which R^(p11) and R^(p12) are attached may be a (R)-chiralcenter. In other embodiments, the carbon to which R^(p11) and R^(p12)are attached may be a (S)-chiral center.

Examples of suitable

groups include the following:

The nucleobase can vary. In some embodiments, B¹ can be uracil. In someembodiments, B¹ can be an optionally substituted

In some embodiments, B¹ can be unsubstituted

In other embodiments, B¹ can be an optionally substituted

In some embodiments, B¹ can be unsubstituted

In some embodiments, R^(6A) can be an optionally substituted C₁₋₆ alkyl.For example, R^(6A) can be methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, pentyl (branched and straight-chained) or hexyl(branched and straight-chained). In other embodiments, R^(6A) can be anoptionally substituted C₃₋₆ cycloalkyl, for example, optionallysubstituted variants of the following: cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.

In some embodiments, B¹ can be guanine. In some embodiments, B can be anoptionally substituted

In other embodiments, B¹ can be an optionally substituted

wherein R^(6B) can be selected from hydrogen, an unsubstituted C₁₋₆alkyl, an unsubstituted C₃₋₆ alkenyl, an unsubstituted C₃₋₆ alkynyl andan unsubstituted C₃₋₆ cycloalkyl. In some embodiments, B¹ can beunsubstituted

In some embodiments, R^(6B) can be an unsubstituted C₁₋₆ alkyl. Forexample, R^(6B) can be methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, pentyl (branched and straight-chained) or hexyl(branched and straight-chained). In some embodiments, R^(6B) can be anunsubstituted C₃₋₆ alkenyl. In other embodiments, R^(6B) can be anunsubstituted C₃₋₆ alkynyl. In still other embodiments, R^(6B) can be anunsubstituted C₃₋₆ cycloalkyl, for example, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.

In some embodiments, B¹ can be an optionally substituted

wherein R^(6C) can be selected from hydrogen, an unsubstituted C₁₋₆alkyl, an unsubstituted C₃₋₆ alkenyl, an unsubstituted C₃₋₆ alkynyl andan unsubstituted C₃₋₆ cycloalkyl. In some embodiments, B¹ can beunsubstituted

In some embodiments, R^(6C) can be hydrogen. In some embodiments, R^(6C)can be an unsubstituted C₁₋₆ alkyl. For example, R^(6C) can be methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl(branched and straight-chained) or hexyl (branched andstraight-chained). In some embodiments, R^(6C) can be an ethyl. In someembodiments, R^(6C) can be an unsubstituted C₃₋₆ alkenyl. In otherembodiments, R^(6C) can be an unsubstituted C₃₋₆ alkynyl. In otherembodiments, R^(6C) can be an unsubstituted C₃₋₆ cycloalkyl, forexample, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In some embodiments, B¹ can be adenine. In some embodiments, B¹ can bean optionally substituted

wherein X¹ can be N (nitrogen) or —CR^(6J); R^(6J) can be selected fromhydrogen, halogen, an optionally substituted C₁₋₆ alkyl, an optionallysubstituted C₂₋₆ alkenyl and an optionally substituted C₂₋₆ alkynyl;R^(6D) can be NHR^(6G); R^(6E) can be hydrogen, halogen or NHR^(6H);R^(6G) can be selected from hydrogen, an optionally substituted C₁₋₆alkyl, an optionally substituted C₃₋₆ alkenyl, an optionally substitutedC₃₋₆ cycloalkyl, —C(═O)R^(A1) and —C(═O)OR^(A2); R^(6H) can be selectedfrom hydrogen, an optionally substituted C₁₋₆ alkyl, an optionallysubstituted C₃₋₆ alkenyl, an optionally substituted C₃₋₆ cycloalkyl,—C(═O)R^(A3) and —C(═O)OR^(A4); R^(A1), R^(A2), R^(A3) and R^(A4) can beindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkenyl, C₆₋₁₀ aryl, heteroaryl, heterocyclyl,aryl(C₁₋₆ alkyl), heteroaryl(C₁₋₆ alkyl) and heterocyclyl(C₁₋₆ alkyl).In some embodiments, X¹ can be N (nitrogen). In other embodiments, X¹can be —CR^(6I), wherein CR^(6I) can be selected from hydrogen, halogen,an optionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆alkenyl and an optionally substituted C₂₋₆ alkynyl. In some embodiments,X¹ can be CH. In some embodiments, R^(6D) and R^(6E) can be both NH₂. Inother embodiments, at least one of R^(6D) and R^(6E) can be NH₂. In someembodiments, R^(6D) can be NHR^(6G), wherein R^(6G) can be an optionallysubstituted C₁₋₆ alkyl. In some embodiments, R^(6E) can be hydrogen. Inother embodiments, R^(6E) can be halogen. In still other embodiments,R^(6E) can be NHR^(6H), wherein R^(6H) can be an optionally substitutedC₁₋₆ alkyl. In other embodiments, R^(6D) can be NHR^(6G), wherein R^(6G)can be selected from an optionally substituted C₃₋₆ alkenyl, anoptionally substituted C₃₋₆ cycloalkyl, —C(═O)R^(A1) and —C(═O)OR^(A2).In other embodiments, R^(6E) can be NHR^(6H), wherein R^(6H) can beselected from an optionally substituted C₃₋₆ alkenyl, an optionallysubstituted C₃₋₆ cycloalkyl, —C(═O)R^(A3) and —C(═O)OR^(A4). In someembodiments, R^(6D) and R^(6E) can be the same. In other embodiments,R^(6D) and R^(6E) can be different.

In some embodiments, B¹ can be cytosine. In some embodiments, B¹ can bean optionally substituted

wherein R^(6F) can be NHR^(6I); R^(6I) can be selected hydrogen, anoptionally substituted C₁₋₆ alkyl, an optionally substituted C₃₋₆alkenyl, an optionally substituted C₃₋₆ cycloalkyl, —C(═O)R^(A5) and—C(═O)OR^(A6); and R^(A5) and R^(A6) are independently selected from thegroup consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkenyl, C₆₋₁₀ aryl, heteroaryl, heterocyclyl,aryl(C₁₋₆ alkyl), heteroaryl(C₁₋₆ alkyl) and heterocyclyl(C₁₋₆ alkyl).In some embodiments, R^(6F) can be NH₂. In other embodiments, R^(6F) canbe NHR^(6I), wherein R^(6I) can be an optionally substituted C₁₋₆ alkyl,an optionally substituted C₃₋₆ alkenyl or an optionally substituted C₃₋₆cycloalkyl. In still other embodiments, R^(6F) can be NHR^(6I), whereinR^(6I) can be —C(═O)R^(A5) or —C(═O)OR^(A6). When R^(6I) is —C(═O)R^(A5)or —C(═O)OR^(A6), R^(A5) and R^(A6) can be C₁₋₆ alkyl, C₂₋₆ alkenyl orC₂₋₆ alkynyl. R^(A5) and R^(A6) can also be C₃₋₆ cycloalkyl, C₃₋₆cycloalkenyl, C₆₋₁₀ aryl or heteroaryl, heterocyclyl. Additionally,R^(A5) and R^(A6) can be aryl(C₁₋₆ alkyl), heteroaryl(C₁₋₆ alkyl) orheterocyclyl(C₁₋₆ alkyl).

In some embodiments, Z¹ can be O (oxygen). In other embodiments, Z¹ canbe S (sulfur).

In some embodiments, R² is not halo. In some embodiments, R² is notfluoro. In some embodiments, R^(5B) is not an —O-optionally substitutedaryl. In some embodiments, R^(5B) is not an —O-unsubstituted aryl. Insome embodiments, R^(5A) is not N-alanine isopropyl ester. In someembodiments, R¹ is not an optionally substituted C₁₋₆ alkyl. Forexample, R¹ is not an unsubstituted C₁₋₆ alkyl, such as methyl. In someembodiments, B¹ is not an optionally substituted uracil, for example, ahalo-substituted uracil. In some embodiment, when both -------- are eachabsent; R^(p) is absent; R³ is OH or —OC(═O)R⁸; R² is F; and R¹ ismethyl, ethyl or ethenyl; then R⁴ cannot be selected from H and

wherein R^(5B) is an —O-unsubstituted aryl; R^(5A) is

and Z¹ is oxygen. In some embodiments, R² is not halo (such as fluoro)when B¹ is uracil. In some embodiments, a compound of Formula (I) is nota compound in WO 2013/092481 (filed Dec. 17, 2012).

Example structures of a compound of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing. In someembodiments of this paragraph, R³ can be OH. In some embodiments of thisparagraph, R^(6C) can be an unsubstituted C₁₋₆ alkyl, such as CH₂CH₃. Insome embodiments of this paragraph, R^(p1) can be —O-unsubstituted C₁₋₆alkyl. In some embodiments, of this paragraph, R⁴ can be H. In otherembodiments, of this paragraph, R⁴ can be a phosphoroamidate group. Instill other embodiments, of this paragraph, R⁴ can be a phosphate group(such as a mono-, di- or tri-phosphate). In yet still other embodiments,of this paragraph, R⁴ can be a thiophosphoroamidate group. In someembodiments, of this paragraph, R⁴ can be thiophosphate group (such asan alpha-thiomono-, alpha-thiodi- or alpha-thiotri-phosphate). In someembodiments of this paragraph, R^(p1) can be —O-ethyl, —O-isopropyl or—O-isobutyl.

Examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

Additional examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

Still further examples of compounds of Formula (I) include thefollowing:

or a pharmaceutically acceptable salt of the foregoing.

Examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

Further examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

Further examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

Additional examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

In some embodiments, a compound of Formula (I) cannot be selected from:

or a pharmaceutically acceptable salt of the foregoing.

As described herein, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can have R⁴ being

R^(5A) being an optionally substituted N-linked amino acid or anoptionally substituted N-linked amino acid ester derivative; and R^(5B)being an —O-optionally substituted aryl, an —O-optionally substitutedheteroaryl, an —O-optionally substituted heterocyclyl, an optionallysubstituted N-linked amino acid or an optionally substituted N-linkedamino acid ester derivative. By neutralizing the charge on the phosphateor thiophosphate, penetration of the cell membrane may be facilitated asa result of the increased lipophilicity of the compound. Once absorbedand taken inside the cell, the groups attached to the phosphorus can beeasily removed by esterases, proteases and/or other enzymes. In someembodiments, the groups attached to the phosphorus can be removed bysimple hydrolysis. Inside the cell, the phosphate thus released may thenbe metabolized by cellular enzymes to the diphosphate or the activetriphosphate. Likewise, the thio-phosphate may be metabolized to thealpha-thiodiphosphate or the alpha-thiotriphosphate. Furthermore, insome embodiments, varying the substituents on a compound describedherein, such as compound of Formula (I), can help maintain the efficacyof such the compound by reducing undesirable effects, such asisomerization.

In some embodiments, the phosphorylation of a thio-monophosphate of acompound of Formula (I), or pharmaceutically acceptable salt thereof,can be stereoselective. For example, a thio-monophosphate of a compoundof Formula (I) can be phosphorylated to give an alpha-thiodiphosphateand/or an alpha-thiotriphosphate compound that can be enriched in the(R) or (S) diastereomer with respect to the 5′-O-phosphorous atom. Forexample, one of the (R) and (S) configuration with respect to the5′-O-phosphorous atom of the alpha-thiodiphosphate and/or thealpha-thiotriphosphate compound can be present in an amount >50%, ≧75%,≧90%, ≧95% or ≧99% compared to the amount of the other of the (R) or (S)configuration with respect to the 5′-O-phosphorous atom. In someembodiments, phosphorylation of a compound of Formula (I), orpharmaceutically acceptable salt thereof, can result in the formation ofa compound that has the (R)-configuration at the 5′-O-phosphorous atom.In some embodiments, phosphorylation of a compound of Formula (I), orpharmaceutically acceptable salt thereof, can result in formation of acompound that has the (S)-configuration at the 5′-O-phosphorous atom.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can act as a chain terminator of HCVreplication. For example, compounds of Formula (I) can contain a moietyat the 2′-carbon position such that once the compound is incorporatedinto an RNA chain of HCV no further elongation is observed to occur. Forexample, a compound of Formula (I) can contain a 2′-carbon modificationwherein R¹ is a non-hydrogen group selected from an optionallysubstituted C₁₋₆ alkyl, an optionally substituted C₂₋₆ alkenyl, anoptionally substituted C₂₋₆ alkynyl and an optionally substituted C₃₋₆cycloalkyl.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can have increased metabolic and/or plasmastability. In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can be more resistant tohydrolysis and/or more resistant to enzymatic transformations. Forexample, a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, can have increased metabolic stability, increased plasmastability, can be more resistant to hydrolysis and/or can be moreresistant to enzymatic transformations compared to a compound that isidentical in structure but for having a hydrogen in place of the fluoroat the 4′-position. In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can have improved properties.A non-limiting list of example properties include, but are not limitedto, increased biological half-life, increased bioavailability, increasepotency, a sustained in vivo response, increased dosing intervals,decreased dosing amounts, decreased cytotoxicity, reduction in requiredamounts for treating disease conditions, reduction in viral load,reduction in time to seroconversion (i.e., the virus becomesundetectable in patient serum), increased sustained viral response, areduction of morbidity or mortality in clinical outcomes, increasedsubject compliance, decreased liver conditions (such as liver fibrosis,liver cirrhosis and/or liver cancer), and compatibility with othermedications. In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can have a biologicalhalf-life of greater than 24 hours. In some embodiments, a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, can have abiological half-life greater than a compound that is identical instructure but for having a hydrogen in place of the fluoro at the4′-position. In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can have more potent antiviralactivity (for example, a lower EC₅₀ in an HCV replicon assay) ascompared to the current standard of care. In some embodiments, acompound of Formula (I), or a pharmaceutically acceptable salt thereof,does not significantly inhibit mitochondrial function of themitochondrial RNA polymerase. For example, a compound of Formula (I), ora pharmaceutically acceptable salt thereof, is incorporated in the humanmitochondrial RNA polymerase less than 10% compared to the natural5′-triphosphate nucleotide with the same B¹.

Additionally, in some embodiments, the presence of athiophosphoroamidate, phosphoroamidate, thiophosphorbisamidate orphosphorbisamidate in a compound of Formula (I) can increase thestability of the compound by inhibiting its degradation. Also, in someembodiments, the presence of a thiophosphoroamidate, phosphoroamidate,thiophosphorbisamidate or phosphorbisamidate can make the compound moreresistant to cleavage in vivo and provide sustained, extended efficacy.In some embodiments, a thiophosphoroamidate, phosphoroamidate,thiophosphorbisamidate or phosphorbisamidate can facilitate thepenetration of the cell membrane by a compound of Formula (I) by makingthe compound more lipophilic. In some embodiments, athiophosphoroamidate, phosphoroamidate, thiophosphorbisamidate orphosphorbisamidate can have improved oral bioavailability, improvedaqueous stability and/or reduced risk of byproduct-related toxicity. Insome embodiments, for comparison purposes, a compound of Formula (I) canbe compared to a compound that is identical in structure but for havinga hydrogen in place of the fluoro at the 4′-position.

Synthesis

Compounds of Formula (I) and those described herein may be prepared invarious ways. General synthetic routes to the compound of Formula (I),and some examples of starting materials used to synthesize the compoundsof Formula (I) are shown in Scheme 1 and 2, and described herein. Theroutes shown and described herein are illustrative only and are notintended, nor are they to be construed, to limit the scope of the claimsin any manner whatsoever. Those skilled in the art will be able torecognize modifications of the disclosed syntheses and to devisealternate routes based on the disclosures herein; all such modificationsand alternate routes are within the scope of the claims.

Compounds of Formula (I) can be prepared using various methods known tothose skilled in the art. Examples of methods are shown in Schemes 1 and2. Suitable phosphorus containing precursors can be commerciallyobtained or prepared by synthetic methods known to those skilled in theart. Examples of general structures of phosphorus containing precursorsare shown in Schemes 1 and 2, and include phosphorochloridates andthiophosphorochloridates. Suitable phosphorochloridates andthiophosphorochloridates are commercially available and/or can besynthetically prepared.

One method for forming a compound of Formula (I) is shown in Scheme 1.In Scheme 1, R^(1a), R^(2a), R^(3a) and B^(1a) can be the same as R¹,R², R³ and B¹ as described herein for Formula (I). In some embodiments,a compound of Formula (I) can be generated from a compound of Formula(A) and a compound of Formula (B) or a compound of Formula (A) and acompound of Formula (C) using an organometallic reagent, such as aGrignard reagent. Suitable Grignard reagents are known to those skilledin the art and include, but are not limited to, alkylmagnesium chloridesand alkylmagnesium bromides. In other embodiments, an appropriate basecan be used to form a compound of Formula (I). Examples of suitablebases include, but are not limited to, an amine base, such as analkylamine (including mono-, di- and tri-alkylamines (e.g.,triethylamine)), optionally substituted pyridines (e.g. collidine) andoptionally substituted imidazoles (e.g., N-methylimidazole)).

When compounds of Formula (I) has Z¹ being sulfur, the sulfur can beadded in various manners. In some embodiments, the sulfur can be part ofthe phosphorus containing precursor, for example,

Alternatively, one of the oxygens attached to the phosphorus can beexchanged with a sulfur using a sulfurization reagent. Suitablesulfurization agents are known to those skilled in the art, and include,but are not limited to, elemental sulfur, Lawesson's reagent,cyclooctasulfur, 3H-1,2-Benzodithiole-3-one-1,1-dioxide (Beaucage'sreagent),3-((N,N-dimethylaminomethylidene)amino)-3H-1,2,4-dithiazole-5-thione(DDTT) and bis(3-triethoxysilyl)propyl-tetrasulfide (TEST).

A phosphorus containing precursor can be coupled to the nucleoside, forexample, a compound of Formula (A). Following the coupling of thephosphorus containing precursor, any leaving groups can be cleaved undersuitable conditions, such as hydrolysis. In Scheme 2, R^(1a), R^(2a),R^(3a) and B^(1a) can be the same as R¹, R², R³ and B¹ as describedherein for Formula (I). Further phosphorus containing groups can beadded using methods known to those skilled in the art, for example usinga pyrophosphate. If desired, one or more bases can be used during theaddition of each phosphorus-containing group. Examples of suitable basesare described herein.

As described herein, in some embodiments, R² and R³ can be each anoxygen atom, wherein the oxygen atoms are linked together by a carbonylgroups. The —O—C(═O)—O— group can be formed using methods known to thoseskilled in the art. For example, a compound of Formula (I), wherein R²and R³ are both hydroxy groups, can be treated with1,1′-carbonyldiimidazole (CDI).

In some embodiments, R² and/or R³ can be —OC(═O)R¹² and —OC(═O)R⁸,respectively. The —OC(═O)R¹² and —OC(═O)R⁸ groups can be formed at the2′- and 3′-positions using various methods known to those skilled in theart. As an example, a compound of Formula (I), wherein R² and R³ areboth hydroxy groups, can be treated with an alkyl anhydride (e.g.,acetic anhydride and propionic anhydride) or an alkyl acid chloride(e.g., acetylchloride). If desired, a catalyst can be used to facilitatethe reaction. An example of suitable catalyst is 4-dimethylaminopyridine(DMAP). Alternatively, the —OC(═O)R¹² and —OC(═O)R⁸ groups can be formedat the 2′- and 3′-positions by reacting an alkyl acid (e.g. acetic acidand propionic acid) in the presences of a carbodiimide or a couplingreagent. Examples of carbodiimides include, but are not limited to,N,N′-dicyclohexylcarbodiimide (DCC), N,N′-diisopropylcarbodiimide (DIC)and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC).

To reduce the formation of side products, one or more the groupsattached to the pentose ring can be protected with one or more suitableprotecting groups. As an example, if R² and/or R³ is/are hydroxygroup(s), the hydroxy group(s) can be protected with suitable protectinggroups, such as triarylmethyl and/or silyl groups. Examples oftriarylmethyl groups include but are not limited to, trityl,monomethoxytrityl (MMTr), 4,4′-dimethoxytrityl (DMTr),4,4′,4″-trimethoxytrityl (TMTr), 4,4′,4″-tris-(benzoyloxy)trityl (TBTr),4,4′,4″-tris(4,5-dichlorophthalimido)trityl (CPTr),4,4′,4″-tris(levulinyloxy)trityl (TLTr),p-anisyl-1-naphthylphenylmethyl, di-o-anisyl-1-naphthylmethyl,p-tolyldipheylmethyl, 3-(imidazolylmethyl)-4,4′-dimethoxytrityl,9-phenylxanthen-9-yl (Pixyl), 9-(p-methoxyphenyl) xanthen-9-yl (Mox),4-decyloxytrityl, 4-hexadecyloxytrityl, 4,4′-dioctadecyltrityl,9-(4-octadecyloxyphenyl) xanthen-9-yl,1,1′-bis-(4-methoxyphenyl)-1′-pyrenylmethyl,4,4′,4″-tris-(tert-butylphenyl)methyl (TTTr) and4,4′-di-3,5-hexadienoxytrityl. Examples of suitable silyl groups aredescribed herein and include trimethylsilyl (TMS),tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS),tert-butyldiphenylsilyl (TBDPS), tri-iso-propylsilyloxymethyl and[2-(trimethylsilyl)ethoxy]methyl. Alternatively, R² and/or R³ can beprotected by a single achiral or chiral protecting group, for example,by forming an orthoester, a cyclic acetal or a cyclic ketal. Suitableorthoesters include methoxymethylene acetal, ethoxymethylene acetal,2-oxacyclopentylidene orthoester, dimethoxymethylene orthoester,1-methoxyethylidene orthoester, 1-ethoxyethylidene orthoester,methylidene orthoester, phthalide orthoester 1,2-dimethoxyethylideneorthoester, and alpha-methoxybenzylidene orthoester; suitable cyclicacetals include methylene acetal, ethylidene acetal, t-butylmethylideneacetal, 3-(benzyloxy)propyl acetal, benzylidene acetal,3,4-dimethoxybenzylidene acetal and p-acetoxybenzylidene acetal; andsuitable cyclic ketals include 1-t-butylethylidene ketal,1-phenylethylidene ketal, isopropylidene ketal, cyclopentylidene ketal,cyclohexylidene ketal, cycloheptylidene ketal and1-(4-methoxyphenyl)ethylidene ketal.

Pharmaceutical Compositions

Some embodiments described herein relates to a pharmaceuticalcomposition, that can include an effective amount of one or morecompounds described herein (e.g., a compound of Formula (I)), or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable carrier, diluent, excipient or combination thereof. In someembodiments, the pharmaceutical composition can include a singlediastereomer of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, (for example, a single diastereomer is presentin the pharmaceutical composition at a concentration of greater than 99%compared to the total concentration of the other diastereomers). Inother embodiments, the pharmaceutical composition can include a mixtureof diastereomers of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof. For example, the pharmaceutical composition caninclude a concentration of one diastereomer of >50%, ≧60%, ≧70%, ≧80%,≧90%, ≧95%, or ≧98%, as compared to the total concentration of the otherdiastereomers. In some embodiments, the pharmaceutical compositionincludes a 1:1 mixture of two diastereomers of a compound of Formula(I), or a pharmaceutically acceptable salt thereof.

The term “pharmaceutical composition” refers to a mixture of one or morecompounds disclosed herein with other chemical components, such asdiluents or carriers. The pharmaceutical composition facilitatesadministration of the compound to an organism. Pharmaceuticalcompositions can also be obtained by reacting compounds with inorganicor organic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonicacid, p-toluenesulfonic acid and salicylic acid. Pharmaceuticalcompositions will generally be tailored to the specific intended routeof administration. A pharmaceutical composition is suitable for humanand/or veterinary applications.

The term “physiologically acceptable” defines a carrier, diluent orexcipient that does not abrogate the biological activity and propertiesof the compound.

As used herein, a “carrier” refers to a compound that facilitates theincorporation of a compound into cells or tissues. For example, withoutlimitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrierthat facilitates the uptake of many organic compounds into cells ortissues of a subject.

As used herein, a “diluent” refers to an ingredient in a pharmaceuticalcomposition that lacks pharmacological activity but may bepharmaceutically necessary or desirable. For example, a diluent may beused to increase the bulk of a potent drug whose mass is too small formanufacture and/or administration. It may also be a liquid for thedissolution of a drug to be administered by injection, ingestion orinhalation. A common form of diluent in the art is a buffered aqueoussolution such as, without limitation, phosphate buffered saline thatmimics the composition of human blood.

As used herein, an “excipient” refers to an inert substance that isadded to a pharmaceutical composition to provide, without limitation,bulk, consistency, stability, binding ability, lubrication,disintegrating ability etc., to the composition. A “diluent” is a typeof excipient.

The pharmaceutical compositions described herein can be administered toa human patient per se, or in pharmaceutical compositions where they aremixed with other active ingredients, as in combination therapy, orcarriers, diluents, excipients or combinations thereof. Properformulation is dependent upon the route of administration chosen.Techniques for formulation and administration of the compounds describedherein are known to those skilled in the art.

The pharmaceutical compositions disclosed herein may be manufactured ina manner that is itself known, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or tableting processes. Additionally, theactive ingredients are contained in an amount effective to achieve itsintended purpose. Many of the compounds used in the pharmaceuticalcombinations disclosed herein may be provided as salts withpharmaceutically compatible counterions.

Multiple techniques of administering a compound exist in the artincluding, but not limited to, oral, rectal, topical, aerosol, injectionand parenteral delivery, including intramuscular, subcutaneous,intravenous, intramedullary injections, intrathecal, directintraventricular, intraperitoneal, intranasal and intraocularinjections.

One may also administer the compound in a local rather than systemicmanner, for example, via injection of the compound directly into theinfected area, often in a depot or sustained release formulation.Furthermore, one may administer the compound in a targeted drug deliverysystem, for example, in a liposome coated with a tissue-specificantibody. The liposomes will be targeted to and taken up selectively bythe organ.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration. The pack or dispensermay also be accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, may be the labeling approvedby the U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. Compositions that can include a compounddescribed herein formulated in a compatible pharmaceutical carrier mayalso be prepared, placed in an appropriate container, and labeled fortreatment of an indicated condition.

Methods of Use

Some embodiments disclosed herein relate to a method of treating and/orameliorating a disease or condition that can include administering to asubject an effective amount of one or more compounds described herein,such as a compound of Formula (I), or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition that includes a compounddescribed herein, or a pharmaceutically acceptable salt thereof. Otherembodiments disclosed herein relate to a method of treating and/orameliorating a disease or condition that can include administering to asubject identified as suffering from the disease or condition aneffective amount of one or more compounds described herein, such as acompound of Formula (I), or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition that includes a compound describedherein, or a pharmaceutically acceptable salt thereof.

Some embodiments disclosed herein relates to a method of ameliorating ortreating a HCV infection that can include administering to a subjectidentified as suffering from a HCV infection an effective amount of oneor more compounds described herein (for example, a compound of Formula(I)), or a pharmaceutical composition that includes one or morecompounds described herein, or a pharmaceutically acceptable saltthereof. Other embodiments described herein relate to using one or morecompounds described herein, or a pharmaceutically acceptable salt of acompound described herein, in the manufacture of a medicament forameliorating and/or treating a HCV infection that can includeadministering to a subject identified as suffering from a HCV infectionan effective amount of one or more compounds described herein. Stillother embodiments described herein relate to one or more compoundsdescribed herein, or a pharmaceutically acceptable salt of a compounddescribed herein, that can be used for ameliorating and/or treating aHCV infection by administering to a subject identified as suffering froma HCV infection an effective amount of one or more compounds describedherein.

Some embodiments disclosed herein relate to methods of amelioratingand/or treating a HCV infection that can include contacting a cellinfected with the hepatitis C virus with an effective amount of one ormore compounds described herein, or a pharmaceutically acceptable saltof a compound described herein, or a pharmaceutical composition thatincludes one or more compounds described herein, or a pharmaceuticallyacceptable salt thereof. Other embodiments described herein relate tousing one or more compounds described herein, or a pharmaceuticallyacceptable salt of a compound described herein, in the manufacture of amedicament for ameliorating and/or treating a HCV infection that caninclude contacting a cell infected with the hepatitis C virus with aneffective amount of said compound(s). Still other embodiments describedherein relate to one or more compounds described herein, or apharmaceutically acceptable salt of a compound described herein, thatcan be used for ameliorating and/or treating a HCV infection bycontacting a cell infected with the hepatitis C virus with an effectiveamount of said compound(s).

Some embodiments disclosed herein relate to methods of inhibitingreplication of a hepatitis C virus that can include contacting a cellinfected with the hepatitis C virus with an effective amount of one ormore compounds described herein, or a pharmaceutically acceptable saltof a compound described herein, or a pharmaceutical composition thatincludes one or more compounds described herein, or a pharmaceuticallyacceptable salt thereof. Other embodiments described herein relate tousing one or more compounds described herein, or a pharmaceuticallyacceptable salt of a compound described herein, in the manufacture of amedicament for inhibiting replication of a hepatitis C virus that caninclude contacting a cell infected with the hepatitis C virus with aneffective amount of said compound(s). Still other embodiments describedherein relate to a compound described herein, or a pharmaceuticallyacceptable salt of a compound described herein, that can be used forinhibiting replication of a hepatitis C virus by contacting a cellinfected with the hepatitis C virus with an effective amount of saidcompound(s).

In some embodiments, the compound can be a compound of Formula (I), or apharmaceutical acceptable salt thereof, wherein R⁴ is hydrogen. In otherembodiments, the compound can be a compound of Formula (I), whereincompound of Formula (I) is a mono, di, or triphosphate, or apharmaceutically acceptable salt of the foregoing. In still otherembodiments, the compound can be a compound of Formula (I), whereincompound of Formula (I) is a thiomonophosphate, alpha-thiodiphosphate,or alpha-thiotriphosphate, or a pharmaceutically acceptable salt of theforegoing. In yet still other embodiments, the compound can be acompound of Formula (I), wherein compound of Formula (I) isphosphoroamidate or phosphorbisamidate, or a pharmaceutically acceptablesalt of the foregoing. In some embodiments, the compound can be acompound of Formula (I), wherein compound of Formula (I) isthiophosphoroamidate or thiophosphorbisamidate, or a pharmaceuticallyacceptable salt of the foregoing. In some embodiments, the compound ofFormula (I), or a pharmaceutical acceptable salt thereof, that can beused to ameliorating and/or treating a viral infection (for example, aHCV infection) and/or inhibit replication of a virus (such as a HCVvirus) can be any of the embodiments provided in any of the embodimentsdescribed in paragraphs [0090]-[0138].

HCV is an enveloped positive strand RNA virus in the Flaviviridaefamily. There are various nonstructural proteins of HCV, such as NS2,NS3, NS4, NS4A, NS4B, NS5A and NS5B. NS5B is believed to be anRNA-dependent RNA polymerase involved in the replication of HCV RNA.

Some embodiments described herein relate to a method of inhibiting NS5Bpolymerase activity that can include contacting a cell infected withhepatitis C virus with an effective amount of a compound of Formula (I),or a pharmaceutical acceptable salt thereof. Some embodiments describedherein relate to a method of inhibiting NS5B polymerase activity thatcan include administering to a subject infected with hepatitis C virusan effective amount of a compound of Formula (I), or a pharmaceuticalacceptable salt thereof. In some embodiments, a compound of Formula (I),or a pharmaceutically acceptable salt thereof, can inhibit a RNAdependent RNA polymerase, and thus, inhibit the replication of HCV RNA.In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can inhibit a HCV polymerase (for example, NS5Bpolymerase).

Some embodiments described herein relate to a method of treating acondition selected from liver fibrosis, liver cirrhosis and liver cancerin a subject suffering from one or more of the aforementioned liverconditions that can include administering to the subject an effectiveamount of a compound or a pharmaceutical composition described herein(for example, a compound of Formula (I), or a pharmaceutical acceptablesalt thereof), wherein the liver condition is caused by a HCV infection.Some embodiments described herein relate to a method of increasing liverfunction in a subject having a HCV infection that can includeadministering to the subject an effective amount of a compound or apharmaceutical composition described herein (for example, a compound ofFormula (I), or a pharmaceutical acceptable salt thereof). Alsocontemplated is a method for reducing or eliminating furthervirus-caused liver damage in a subject having an HCV infection byadministering to the subject an effective amount of a compound or apharmaceutical composition described herein (for example, a compound ofFormula (I), or a pharmaceutical acceptable salt thereof). In someembodiments, this method can include slowing or halting the progressionof liver disease. In other embodiments, the course of the disease can bereversed, and stasis or improvement in liver function is contemplated.In some embodiments, liver fibrosis, liver cirrhosis and/or liver cancercan be treated; liver function can be increased; virus-caused liverdamage can be reduced or eliminated; progression of liver disease can beslowed or halted; the course of the liver disease can be reversed and/orliver function can be improved or maintained by contacting a cellinfected with hepatitis C virus with an effective amount of a compounddescribed herein (for example, a compound of Formula (I), or apharmaceutically acceptable salt thereof.)

There are a variety of genotypes of HCV, and a variety of subtypeswithin each genotype. For example, at present it is known that there areeleven (numbered 1 through 11) main genotypes of HCV, although othershave classified the genotypes as 6 main genotypes. Each of thesegenotypes is further subdivided into subtypes (1a-1c; 2a-2c; 3a-3b;4a-4e; 5a; 6a; 7a-7b; 8a-8b; 9a; 10a; and 11a). In some embodiments, aneffective amount of a compound of Formula (I), or a pharmaceuticalacceptable salt thereof, or a pharmaceutical composition that includesan effective amount of a compound of Formula (I), or a pharmaceuticalacceptable salt thereof, can be effective to treat at least one genotypeof HCV. In some embodiments, a compound described herein (for example, acompound of Formula (I), or a pharmaceutical acceptable salt thereof)can be effective to treat all 11 genotypes of HCV. In some embodiments,a compound described herein (for example, a compound of Formula (I), ora pharmaceutical acceptable salt thereof) can be effective to treat 3 ormore, 5 or more, 7 or more, or 9 or more genotypes of HCV. In someembodiments, a compound of Formula (I), or a pharmaceutical acceptablesalt thereof can be more effective against a larger number of HCVgenotypes than the standard of care. In some embodiments, a compound ofFormula (I), or a pharmaceutical acceptable salt thereof, can be moreeffective against a particular HCV genotype than the standard of care(such as genotype 1, 2, 3, 4, 5 and/or 6).

Various indicators for determining the effectiveness of a method fortreating a HCV infection are known to those skilled in the art. Examplesof suitable indicators include, but are not limited to, a reduction inviral load, a reduction in viral replication, a reduction in time toseroconversion (virus undetectable in patient serum), an increase in therate of sustained viral response to therapy, a reduction of morbidity ormortality in clinical outcomes, a reduction in the rate of liverfunction decrease; stasis in liver function; improvement in liverfunction; reduction in one or more markers of liver dysfunction,including alanine transaminase, aspartate transaminase, total bilirubin,conjugated bilirubin, gamma glutamyl transpeptidase and/or otherindicator of disease response. Similarly, successful therapy with aneffective amount of a compound or a pharmaceutical composition describedherein (for example, a compound of Formula (I), or a pharmaceuticalacceptable salt thereof) can reduce the incidence of liver cancer in HCVinfected subjects.

In some embodiments, an effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, is an amount that iseffective to reduce HCV viral titers to undetectable levels, forexample, to about 100 to about 500, to about 50 to about 100, to about10 to about 50, or to about 15 to about 25 international units/mL serum.In some embodiments, an effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, is an amount that iseffective to reduce HCV viral load compared to the HCV viral load beforeadministration of the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof. For example, wherein the HCV viral load ismeasured before administration of the compound of Formula (I), or apharmaceutically acceptable salt thereof, and again after completion ofthe treatment regime with the compound of Formula (I), or apharmaceutically acceptable salt thereof (for example, 1 month aftercompletion). In some embodiments, an effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, can be anamount that is effective to reduce HCV viral load to lower than about 25international units/mL serum. In some embodiments, an effective amountof a compound of Formula (I), or a pharmaceutically acceptable saltthereof, is an amount that is effective to achieve a reduction in HCVviral titer in the serum of the subject in the range of about 1.5-log toabout a 2.5-log reduction, about a 3-log to about a 4-log reduction, ora greater than about 5-log reduction compared to the viral load beforeadministration of the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof. For example, the HCV viral load can be measuredbefore administration of the compound of Formula (I), or apharmaceutically acceptable salt thereof, and again after completion ofthe treatment regime with the compound of Formula (I), or apharmaceutically acceptable salt thereof (for example, 1 month aftercompletion).

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can result in at least a 1, 2, 3, 4, 5, 10, 15,20, 25, 50, 75, 100-fold or more reduction in the replication of thehepatitis C virus relative to pre-treatment levels in a subject, asdetermined after completion of the treatment regime (for example, 1month after completion). In some embodiments, a compound of Formula (I),or a pharmaceutically acceptable salt thereof, can result in a reductionof the replication of the hepatitis C virus relative to pre-treatmentlevels in the range of about 2 to about 5 fold, about 10 to about 20fold, about 15 to about 40 fold, or about 50 to about 100 fold. In someembodiments, a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, can result in a reduction of the hepatitis C virusreplication in the range of 1 to 1.5 log, 1.5 log to 2 log, 2 log to 2.5log, 2.5 to 3 log, 3 log to 3.5 log or 3.5 to 4 log more reduction ofthe hepatitis C virus replication compared to the reduction of thehepatitis C virus reduction achieved by pegylated interferon incombination with ribavirin, administered according to the standard ofcare, or may achieve the same reduction as that standard of care therapyin a shorter period of time, for example, in one month, two months, orthree months, as compared to the reduction achieved after six months ofstandard of care therapy with ribavirin and pegylated interferon.

In some embodiments, an effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, is an amount that iseffective to achieve a sustained viral response, for example,non-detectable or substantially non-detectable HCV RNA (e.g., less thanabout 500, less than about 200, less than about 100, less than about 25,or less than about 15 international units per milliliter serum) is foundin the subject's serum for a period of at least about one month, atleast about two months, at least about three months, at least about fourmonths, at least about five months, or at least about six monthsfollowing cessation of therapy.

In some embodiments, an effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, can reduce a level of amarker of liver fibrosis by at least about 10%, at least about 20%, atleast about 25%, at least about 30%, at least about 35%, at least about40%, at least about 45%, at least about 50%, at least about 55%, atleast about 60%, at least about 65%, at least about 70%, at least about75%, or at least about 80%, or more, compared to the level of the markerin an untreated subject, or to a placebo-treated subject. Methods ofmeasuring serum markers are known to those skilled in the art andinclude immunological-based methods, e.g., enzyme-linked immunosorbentassays (ELISA), radioimmunoassays, and the like, using antibody specificfor a given serum marker. A non-limiting list of examples of markersincludes measuring the levels of serum alanine aminotransferase (ALT),aspartate aminotransferase (AST), alkaline phosphatase (ALP),gamma-glutamyl transpeptidase (GGT) and total bilirubin (TBIL) usingknown methods. In general, an ALT level of less than about 45 IU/L(international units/liter), an AST in the range of 10-34 IU/L, ALP inthe range of 44-147 IU/L, GGT in the range of 0-51 IU/L, TBIL in therange of 0.3-1.9 mg/dL is considered normal. In some embodiments, aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can be an amount effective to reduce ALT, AST,ALP, GGT and/or TBIL levels to with what is considered a normal level.

Subjects who are clinically diagnosed with HCV infection include “naïve”subjects (e.g., subjects not previously treated for HCV, particularlythose who have not previously received IFN-alpha-based and/orribavirin-based therapy) and individuals who have failed prior treatmentfor HCV (“treatment failure” subjects). Treatment failure subjectsinclude “non-responders” (i.e., subjects in whom the HCV titer was notsignificantly or sufficiently reduced by a previous treatment for HCV(≦0.5 log IU/mL), for example, a previous IFN-alpha monotherapy, aprevious IFN-alpha and ribavirin combination therapy, or a previouspegylated IFN-alpha and ribavirin combination therapy); and “relapsers”(i.e., subjects who were previously treated for HCV, for example, whoreceived a previous IFN-alpha monotherapy, a previous IFN-alpha andribavirin combination therapy, or a previous pegylated IFN-alpha andribavirin combination therapy, whose HCV titer decreased, andsubsequently increased).

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can be administered to a treatment failuresubject suffering from HCV. In some embodiments, a compound of Formula(I), or a pharmaceutically acceptable salt thereof, can be administeredto a non-responder subject suffering from HCV. In some embodiments, acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be administered to a relapsed subject suffering from HCV.

After a period of time, infectious agents can develop resistance to oneor more therapeutic agents. The term “resistance” as used herein refersto a viral strain displaying a delayed, lessened and/or null response toa therapeutic agent(s). For example, after treatment with an antiviralagent, the viral load of a subject infected with a resistant virus maybe reduced to a lesser degree compared to the amount in viral loadreduction exhibited by a subject infected with a non-resistant strain.In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can be administered to a subject infected withan HCV strain that is resistant to one or more different anti-HCV agents(for example, an agent used in a conventional standard of care). In someembodiments, development of resistant HCV strains is delayed when asubject is treated with a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, compared to the development of HCV strainsresistant to other HCV drugs (such as an agent used in a conventionalstandard of care).

In some embodiments, an effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, can be administered to asubject for whom other anti-HCV medications are contraindicated. Forexample, administration of pegylated interferon alpha in combinationwith ribavirin is contraindicated in subjects with hemoglobinopathies(e.g., thalassemia major, sickle-cell anemia) and other subjects at riskfrom the hematologic side effects of current therapy. In someembodiments, a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, can be provided to a subject that is hypersensitive tointerferon and/or ribavirin.

Some subjects being treated for HCV experience a viral load rebound. Theterm “viral load rebound” as used herein refers to a sustained ≧0.5 logIU/mL increase of viral load above nadir before the end of treatment,where nadir is a ≧0.5 log IU/mL decrease from baseline. In someembodiments, a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, can be administered to a subject experiencing viral loadrebound, or can prevent such viral load rebound when used to treat thesubject.

The standard of care for treating HCV has been associated with severalside effects (adverse events). In some embodiments, a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, can decreasethe number and/or severity of side effects that can be observed in HCVpatients being treated with ribavirin and pegylated interferon accordingto the standard of care. Examples of side effects include, but are notlimited to fever, malaise, tachycardia, chills, headache, arthralgias,myalgias, fatigue, apathy, loss of appetite, nausea, vomiting, cognitivechanges, asthenia, drowsiness, lack of initiative, irritability,confusion, depression, severe depression, suicidal ideation, anemia, lowwhite blood cell counts, and thinning of hair. In some embodiments, acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be provided to a subject that discontinued a HCV therapy because ofone or more adverse effects or side effects associated with one or moreother HCV agents (for example, an agent used in a conventional standardof care).

Table 1 provides some embodiments of the percentage improvement obtainedusing a compound of Formula (I), or a pharmaceutically acceptable saltthereof, as compared to the standard of care. Examples include thefollowing: in some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, results in a percentage ofnon-responders that is 10% less than the percentage of non-respondersreceiving the standard of care; in some embodiments, a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, results in anumber of side effects that is in the range of about 10% to about 30%less than compared to the number of side effects experienced by asubject receiving the standard of care; and in some embodiments, acompound of Formula (I), or a pharmaceutically acceptable salt thereof,results in a severity of a side effect (such as one of those describedherein) that is 25% less than compared to the severity of the same sideeffect experienced by a subject receiving the standard of care. Methodsof quantifying the severity of a side effect are known to those skilledin the art.

TABLE 1 Percentage Percentage Percentage Percentage Number Severity ofnon- of of of viral load of side of side responders relapsers resistancerebound effects effects 10% less 10% less 10% less 10% less 10% less 10%less 25% less 25% less 25% less 25% less 25% less 25% less 40% less 40%less 40% less 40% less 40% less 40% less 50% less 50% less 50% less 50%less 50% less 50% less 60% less 60% less 60% less 60% less 60% less 60%less 70% less 70% less 70% less 70% less 70% less 70% less 80% less 80%less 80% less 80% less 80% less 80% less 90% less 90% less 90% less 90%less 90% less 90% less about 10% about 10% about 10% about 10% to about10% about 10% to about to about to about about 30% to about to about 30%less 30% less 30% less less 30% less 30% less about 20% about 20% about20% about 20% to about 20% about 20% to about to about to about about50% to about to about 50% less 50% less 50% less less 50% less 50% lessabout 30% about 30% about 30% about 30% to about 30% about 30% to aboutto about to about about 70% to about to about 70% less 70% less 70% lessless 70% less 70% less about 20% about 20% about 20% about 20% to about20% about 20% to about to about to about about 80% to about to about 80%less 80% less 80% less less 80% less 80% less

As used herein, a “subject” refers to an animal that is the object oftreatment, observation or experiment. “Animal” includes cold- andwarm-blooded vertebrates and invertebrates such as fish, shellfish,reptiles and, in particular, mammals. “Mammal” includes, withoutlimitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats,cows, horses, primates, such as monkeys, chimpanzees, and apes, and, inparticular, humans. In some embodiments, the subject is human.

As used herein, the terms “treating,” “treatment,” “therapeutic,” or“therapy” do not necessarily mean total cure or abolition of the diseaseor condition. Any alleviation of any undesired signs or symptoms of adisease or condition, to any extent can be considered treatment and/ortherapy. Furthermore, treatment may include acts that may worsen thepatient's overall feeling of well-being or appearance.

The terms “therapeutically effective amount” and “effective amount” areused to indicate an amount of an active compound, or pharmaceuticalagent, that elicits the biological or medicinal response indicated. Forexample, an effective amount of compound can be the amount needed toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated This response may occur in atissue, system, animal or human and includes alleviation of the signs orsymptoms of the disease being treated. Determination of an effectiveamount is well within the capability of those skilled in the art, inview of the disclosure provided herein. The effective amount of thecompounds disclosed herein required as a dose will depend on the routeof administration, the type of animal, including human, being treated,and the physical characteristics of the specific animal underconsideration. The dose can be tailored to achieve a desired effect, butwill depend on such factors as weight, diet, concurrent medication andother factors which those skilled in the medical arts will recognize.

As will be readily apparent to one skilled in the art, the useful invivo dosage to be administered and the particular mode of administrationwill vary depending upon the age, weight, the severity of theaffliction, and mammalian species treated, the particular compoundsemployed, and the specific use for which these compounds are employed.The determination of effective dosage levels, that is the dosage levelsnecessary to achieve the desired result, can be accomplished by oneskilled in the art using routine methods, for example, human clinicaltrials and in vitro studies.

The dosage may range broadly, depending upon the desired effects and thetherapeutic indication. Alternatively dosages may be based andcalculated upon the surface area of the patient, as understood by thoseof skill in the art. Although the exact dosage will be determined on adrug-by-drug basis, in most cases, some generalizations regarding thedosage can be made. The daily dosage regimen for an adult human patientmay be, for example, an oral dose of between 0.01 mg and 3000 mg of eachactive ingredient, preferably between 1 mg and 700 mg, e.g. 5 to 200 mg.The dosage may be a single one or a series of two or more given in thecourse of one or more days, as is needed by the subject. In someembodiments, the compounds will be administered for a period ofcontinuous therapy, for example for a week or more, or for months oryears. In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can be administered lessfrequently compared to the frequency of administration of an agentwithin the standard of care. In some embodiments, a compound of Formula(I), or a pharmaceutically acceptable salt thereof, can be administeredone time per day. For example, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can be administered one timeper day to a subject suffering from a HCV infection. In someembodiments, the total time of the treatment regime with a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, can lesscompared to the total time of the treatment regime with the standard ofcare.

In instances where human dosages for compounds have been established forat least some condition, those same dosages may be used, or dosages thatare between about 0.1% and 500%, more preferably between about 25% and250% of the established human dosage. Where no human dosage isestablished, as will be the case for newly-discovered pharmaceuticalcompositions, a suitable human dosage can be inferred from ED₅₀ or ID₅₀values, or other appropriate values derived from in vitro or in vivostudies, as qualified by toxicity studies and efficacy studies inanimals.

In cases of administration of a pharmaceutically acceptable salt,dosages may be calculated as the free base. As will be understood bythose of skill in the art, in certain situations it may be necessary toadminister the compounds disclosed herein in amounts that exceed, oreven far exceed, the above-stated, preferred dosage range in order toeffectively and aggressively treat particularly aggressive diseases orinfections.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain themodulating effects, or minimal effective concentration (MEC). The MECwill vary for each compound but can be estimated from in vitro data.Dosages necessary to achieve the MEC will depend on individualcharacteristics and route of administration. However, HPLC assays orbioassays can be used to determine plasma concentrations. Dosageintervals can also be determined using MEC value. Compositions should beadministered using a regimen which maintains plasma levels above the MECfor 10-90% of the time, preferably between 30-90% and most preferablybetween 50-90%. In cases of local administration or selective uptake,the effective local concentration of the drug may not be related toplasma concentration.

It should be noted that the attending physician would know how to andwhen to terminate, interrupt, or adjust administration due to toxicityor organ dysfunctions. Conversely, the attending physician would alsoknow to adjust treatment to higher levels if the clinical response werenot adequate (precluding toxicity). The magnitude of an administrateddose in the management of the disorder of interest will vary with theseverity of the condition to be treated and to the route ofadministration. The severity of the condition may, for example, beevaluated, in part, by standard prognostic evaluation methods. Further,the dose and perhaps dose frequency, will also vary according to theage, body weight, and response of the individual patient. A programcomparable to that discussed above may be used in veterinary medicine.

Compounds disclosed herein can be evaluated for efficacy and toxicityusing known methods. For example, the toxicology of a particularcompound, or of a subset of the compounds, sharing certain chemicalmoieties, may be established by determining in vitro toxicity towards acell line, such as a mammalian, and preferably human, cell line. Theresults of such studies are often predictive of toxicity in animals,such as mammals, or more specifically, humans. Alternatively, thetoxicity of particular compounds in an animal model, such as mice, rats,rabbits, or monkeys, may be determined using known methods. The efficacyof a particular compound may be established using several recognizedmethods, such as in vitro methods, animal models, or human clinicaltrials. When selecting a model to determine efficacy, the skilledartisan can be guided by the state of the art to choose an appropriatemodel, dose, route of administration and/or regime.

Combination Therapies

In some embodiments, the compounds disclosed herein, such as a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition that includes a compound described herein, ora pharmaceutically acceptable salt thereof, can be used in combinationwith one or more additional agent(s). Examples of additional agents thatcan be used in combination with a compound of Formula (I), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition that includes a compound of Formula (I), or apharmaceutically acceptable salt thereof, include, but are not limitedto, agents currently used in a conventional standard of care fortreating HCV, HCV protease inhibitors, HCV polymerase inhibitors, NS5Ainhibitors, other antiviral compounds, compounds of Formula (AA),(including pharmaceutically acceptable salts and pharmaceuticalcompositions that can include a compound of Formula (AA), or apharmaceutically acceptable salt thereof), compounds of Formula (BB)(including pharmaceutically acceptable salts and pharmaceuticalcompositions that can include a compound of Formula (BB), or apharmaceutically acceptable salt thereof), compounds of Formula (CC)(including pharmaceutically acceptable salts and pharmaceuticalcompositions that can include a compound of Formula (CC), or apharmaceutically acceptable salt thereof), and/or combinations thereof.In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used with one, two, three or more additional agents describedherein. A non-limiting list of examples of combinations of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition that includes a compound of Formula (I), or apharmaceutically acceptable salt thereof, is provided in Tables A, B, C,D and E.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used in combination with an agent(s) currently used in aconventional standard of care therapy. For example, for the treatment ofHCV, a compound disclosed herein can be used in combination withPegylated interferon-alpha-2a (brand name PEGASYS®) and ribavirin,Pegylated interferon-alpha-2b (brand name PEG-INTRON®) and ribavirin,Pegylated interferon-alpha-2a, Pegylated interferon-alpha-2b, orribavirin.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be substituted for an agent currently used in a conventionalstandard of care therapy. For example, for the treatment of HCV, acompound of Formula (I), or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition that includes a compound of Formula (I),or a pharmaceutically acceptable salt thereof, can be used in place ofribavirin.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used in combination with an interferon, such as a pegylatedinterferon. Examples of suitable interferons include, but are notlimited to, Pegylated interferon-alpha-2a (brand name PEGASYS®),Pegylated interferon-alpha-2b (brand name PEG-INTRON®), interferonalfacon-1 (brand name INFERGEN®), pegylated interferon lambda and/or acombination thereof.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used in combination with a HCV protease inhibitor. A non-limitinglist of example HCV protease inhibitors include the following: VX-950(TELAPREVIR®), MK-5172, ABT-450, BILN-2061, BI-201335, BMS-650032, SCH503034 (BOCEPREVIR®), GS-9256, GS-9451, IDX-320, ACH-1625, ACH-2684,TMC-435, ITMN-191 (DANOPREVIR®) and/or a combination thereof. AdditionalHCV protease inhibitors suitable for use in combination with a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition that includes a compound of Formula (I), or apharmaceutically acceptable salt thereof, include VP-19744, PSI-879,VCH-759/VX-759, HCV-371, IDX-375, GL-60667, JTK-109, PSI-6130, R1479,R-1626, R-7182, MK-0608, INX-8014, INX-8018, A-848837, A-837093,BILB-1941, VCH-916, VCH-716, GSK-71185, GSK-625433, XTL-2125 and thosedisclosed in PCT Publication No. WO 2012/142085, which is herebyincorporated by reference for the limited purpose of its disclosure ofHCV protease inhibitors, HCV polymerase inhibitors and NS5A inhibitors.A non-limiting list of example HCV protease inhibitors includes thecompounds numbered 1001-1016 in FIG. 1.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used in combination with a HCV polymerase inhibitor. In someembodiments, the HCV polymerase inhibitor can be a nucleoside inhibitor.In other embodiments, the HCV polymerase inhibitor can be anon-nucleoside inhibitor. Examples of suitable nucleoside inhibitorsinclude, but are not limited to, RG7128, PSI-7851, PSI-7977, INX-189,PSI-352938, PSI-661, 4′-azidouridine (including known prodrugs of4′-azidouridine), GS-6620, IDX-184, and TMC649128 and/or combinationsthereof. A non-limiting list of example nucleoside inhibitors includescompounds numbered 2001-2012 in FIG. 2. Examples of suitablenon-nucleoside inhibitors include, but are not limited to, ABT-333,ANA-598, VX-222, HCV-796, BI-207127, GS-9190, PF-00868554 (FILIBUVIR®),VX-497 and/or combinations thereof. A non-limiting list of examplenon-nucleoside inhibitors includes the compounds numbered 3001-3014 inFIG. 3. Further HCV polymerase inhibitors suitable for use incombination with a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,include VX-500, VX-813, VBY-376, TMC-435350, EZ-058, EZ-063, GS-9132,ACH-1095, IDX-136, IDX-316, ITMN-8356, ITMN-8347, ITMN-8096, ITMN-7587,VX-985, and those disclosed in PCT Publication No. WO 2012/142085.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used in combination with a NS5A inhibitor. Examples of NS5Ainhibitors include BMS-790052, PPI-461, ACH-2928, GS-5885, BMS-824393and/or combinations thereof. A non-limiting list of example NS5Ainhibitors includes the compounds numbered 4001-4012 in FIG. 4.Additional NS5A inhibitors suitable for use in combination with acompound of Formula (I), or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition that includes a compound of Formula (I),or a pharmaceutically acceptable salt thereof, include A-832, PPI-1301and those disclosed in PCT Publication No. WO 2012/142085.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used in combination with other antiviral compounds. Examples ofother antiviral compounds include, but are not limited to, Debio-025,MIR-122, cyclosporin A and/or combinations thereof. A non-limiting listof example other antiviral compounds includes the compounds numbered5001-5012 in FIG. 5.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used in combination with a compound of Formula (AA), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition that includes a compound of Formula (AA), or apharmaceutically acceptable salt thereof (see, U.S. Publication No.2013/0164261, published Jun. 27, 2013, the contents of which areincorporated by reference in its entirety):

wherein: B^(AA1) can be an optionally substituted heterocyclic base oran optionally substituted heterocyclic base with a protected aminogroup; R^(AA1) can be selected from O⁻, OH, an optionally substitutedN-linked amino acid and an optionally substituted N-linked amino acidester derivative; R^(AA2) be absent or selected from hydrogen, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted heterocyclyl and

wherein R^(AA6), R^(AA7) and R^(AA8) can be independently absent orhydrogen, and n^(AA) can be 0 or 1; provided that when R^(AA1) is O⁻ orOH, then R^(AA2) is absent, hydrogen or

R^(AA3) can be selected from hydrogen, halogen, —OR^(AA9) and—OC(═O)R^(AA10); R^(AA4) can be selected from halogen, —OR^(AA11) and—OC(═O)R^(AA12); or R^(AA3) and R^(AA4) can be both an oxygen atom whichare linked together by a carbonyl group; R^(AA5) can be selected from anoptionally substituted C₂₋₆ alkyl, an optionally substituted C₂₋₆alkenyl, an optionally substituted C₂₋₆ alkynyl and an optionallysubstituted C₃₋₆ cycloalkyl; or R^(AA4) and R′ can form —(C₁₋₆ alkyl)-O—or —O—(C₁₋₆ alkyl)-; R^(AA9) and R^(AA11) can be independently hydrogenor an optionally substituted C₁₋₆ alkyl; and R^(AA10) and R^(AA12) canbe independently an optionally substituted C₁₋₆ alkyl or an optionallysubstituted C₃₋₆ cycloalkyl. A non-limiting list of examples ofcompounds of Formula (AA) includes the compounds numbered 7000-7027 inFIG. 7.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used in combination with a compound of Formula (BB), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition that includes a compound of Formula (BB), or apharmaceutically acceptable salt thereof (see, U.S. Publication No.2012/0165286, published Jun. 28, 2012, the contents of which areincorporated by reference in their entireties):

wherein B^(BB1) can be an optionally substituted heterocyclic base or anoptionally substituted heterocyclic base with a protected amino group;X^(BB) can be O (oxygen) or S (sulfur); R^(BB1) can be selected from—Z^(BB)—R^(BB9), an optionally substituted N-linked amino acid and anoptionally substituted N-linked amino acid ester derivative; Z^(BB) canbe selected from O (oxygen), S (sulfur) and N(R^(BB10)); R^(BB2) andR^(BB3) can be independently selected from hydrogen, an optionallysubstituted C₁₋₆ alkyl, an optionally substituted C₂₋₆ alkenyl, anoptionally substituted C₂₋₆ alkynyl, an optionally substituted C₁₋₆haloalkyl and an optionally substituted aryl(C₁₋₆ alkyl); or R^(BB2) andR^(BB3) can be taken together to form a group selected from anoptionally substituted C₃₋₆ cycloalkyl, an optionally substituted C₃₋₆cycloalkenyl, an optionally substituted C₃₋₆ aryl and an optionallysubstituted C₃₋₆ heteroaryl; R^(BB4) can be selected from hydrogen,halogen, azido, cyano, an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₂₋₆ alkenyl, an optionally substituted C₂₋₆alkynyl and an optionally substituted allenyl; R^(BB5) can be hydrogenor an optionally substituted C₁₋₆ alkyl; R^(BB6) can be selected fromhydrogen, halogen, azido, amino, cyano, an optionally substituted C₁₋₆alkyl, —OR^(BB11) and —OC(═O)R^(BB12); R^(BB7) can be selected fromhydrogen, halogen, azido, cyano, an optionally substituted C₁₋₆ alkyl,—OR^(BB13) and —OC(═O)R^(BB14); R^(BB8) can be selected from hydrogen,halogen, azido, cyano, an optionally substituted C₁₋₆ alkyl, —OR^(BB15)and —OC(═O)RBB¹⁶; R^(BB9) can be selected from an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted heterocyclyl, an optionallysubstituted aryl(C₁₋₆alkyl), an optionally substitutedheteroaryl(C₁₋₆alkyl) and an optionally substitutedheterocyclyl(C₁₋₆alkyl); R^(BB10) can be selected from hydrogen, anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substitutedheterocyclyl, an optionally substituted aryl(C₁₋₆alkyl), an optionallysubstituted heteroaryl(C₁₋₆alkyl) and an optionally substitutedheterocyclyl(C₁₋₆alkyl); R^(BB11), R^(BB13) and R^(BB15) can beindependently hydrogen or an optionally substituted C₁₋₆ alkyl; andR^(BB12), R^(BB14) and R^(BB16) can be independently an optionallysubstituted C₁₋₆ alkyl or an optionally substituted C₃₋₆ cycloalkyl. Insome embodiments, at least one of R^(BB2) and R^(BB3) is not hydrogen. Anon-limiting list of example compounds of Formula (BB) includes thecompound numbered 8000-8016 in FIG. 8.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used in combination with a compound of Formula (CC), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition that includes a compound of Formula (CC), or apharmaceutically acceptable salt thereof (see, U.S. Publication No.2012/0071434, published Mar. 22, 2012, the contents of which areincorporated by reference in its entirety):

wherein B^(CC1) can be an optionally substituted heterocyclic base or anoptionally substituted heterocyclic base with a protected amino group;R^(CC1) can be selected from O⁻, OH, an optionally substituted N-linkedamino acid and an optionally substituted N-linked amino acid esterderivative; R^(CC2) can be selected from an optionally substituted aryl,an optionally substituted heteroaryl, an optionally substitutedheterocyclyl and

wherein R^(CC19), R^(CC20), and R^(CC21) can be independently absent orhydrogen, and n^(CC) can be 0 or 1; provided that when R^(CC1) is O⁻ orOH, then R^(CC2) is

R^(CC3a) and R^(CC3b) can be independently selected from hydrogen,deuterium, an optionally substituted C₁₋₆ alkyl, an optionallysubstituted C₂₋₆ alkenyl, an optionally substituted C₂₋₆ alkynyl, anoptionally substituted C₁₋₆ haloalkyl and aryl(C₁₋₆ alkyl); or R^(CC3a)and R^(CC3b) can be taken together to form an optionally substitutedC₃₋₆ cycloalkyl; R^(CC4) can be selected from hydrogen, azido, anoptionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆alkenyl and an optionally substituted C₂₋₆ alkynyl; R^(CC5) can beselected from hydrogen, halogen, azido, cyano, an optionally substitutedC₁₋₆ alkyl, —OR^(CC10) and —OC(═O)R^(CC11); R^(CC6) can be selected fromhydrogen, halogen, azido, cyano, an optionally substituted C₁₋₆ alkyl,—OR^(CC12) and —OC(═O)R^(CC13); R^(CC7) can be selected from hydrogen,halogen, azido, cyano, an optionally substituted C₁₋₆ alkyl, —OR^(CC14)and —OC(═O)R^(CC15); or R^(CC6) and R^(CC7) can be both oxygen atoms andlinked together by a carbonyl group; R^(CC8) can be selected fromhydrogen, halogen, azido, cyano, an optionally substituted C₁₋₆ alkyl,—OR^(CC16) and —OC(═O)R^(CC17); R^(CC9) can be selected from hydrogen,azido, cyano, an optionally substituted C₁₋₆ alkyl and —OR^(CC18);R^(CC10); R^(CC12); R^(CC14); R^(CC16) and R^(CC18) can be independentlyselected from hydrogen and an optionally substituted C₁₋₆ alkyl; andR^(CC11), R^(CC13); R^(CC15) and R^(CC17) can be independently selectedfrom an optionally substituted C₁₋₆ alkyl and an optionally substitutedC₃₋₆ cycloalkyl. In some embodiments, when R^(CC3a), R^(CC3b); R^(CC4);R^(CC5); R^(CC7); R^(CC8) and R^(CC9) are all hydrogen, then R^(CC6) isnot azido. In some embodiments, R^(CC2) cannot be

when R^(CC3a) is hydrogen, R^(CC3b) is hydrogen, R^(CC4) is H, R^(CC5)is OH or H, R^(CC6) is hydrogen, OH, or —OC(═O)CH₃, R^(CC7) is hydrogen,OH, OCH₃ or —OC(═O)CH₃, R^(CC8) is hydrogen, OH or OCH₃, R^(CC9) is Hand B^(CC1) is an optionally substituted adenine, an optionallysubstituted guanine, an optionally substituted uracil or an optionallysubstituted hypoxanthine. In some embodiments, R^(CC2) cannot be

A non-limiting list of examples of compounds of Formula (CC) includesthe compounds numbered 6000-6078 in FIG. 6.

Some embodiments described herein relate to a method of ameliorating ortreating a HCV infection that can include contacting a cell infectedwith the HCV infection with an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, in combination withone or more agents selected from an interferon, ribavirin, a HCVprotease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, anantiviral compound, a compound of Formula (AA), a compound of Formula(BB) and a compound of Formula (CC), or a pharmaceutically acceptablesalt of any of the aforementioned compounds.

Some embodiments described herein relate to a method of ameliorating ortreating a HCV infection that can include administering to a subjectsuffering from the HCV infection an effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, incombination with one or more agents selected from an interferon,ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5Ainhibitor, an antiviral compound, a compound of Formula (AA), a compoundof Formula (BB) and a compound of Formula (CC), or a pharmaceuticallyacceptable salt of any of the aforementioned compounds.

Some embodiments described herein relate to a method of inhibiting thereplication of a hepatitis C virus that can include contacting a cellinfected with the hepatitis C virus with an effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,in combination with one or more agents selected from an interferon,ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5Ainhibitor, an antiviral compound, a compound of Formula (AA), a compoundof Formula (BB) and a compound of Formula (CC), or a pharmaceuticallyacceptable salt of any of the aforementioned compounds.

Some embodiments described herein relate to a method of inhibiting thereplication of a hepatitis C virus that can include administering to asubject infected with the hepatitis C virus an effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,in combination with one or more agents selected from an interferon,ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5Ainhibitor, an antiviral compound, a compound of Formula (AA), a compoundof Formula (BB) and a compound of Formula (CC), or a pharmaceuticallyacceptable salt of any of the aforementioned compounds.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can be administered with one or more additionalagent(s) together in a single pharmaceutical composition. In someembodiments, a compound of Formula (I), or a pharmaceutically acceptablesalt the thereof, can be administered with one or more additionalagent(s) as two or more separate pharmaceutical compositions. Forexample, a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, can be administered in one pharmaceutical composition, andat least one of the additional agents can be administered in a secondpharmaceutical composition. If there are at least two additional agents,one or more of the additional agents can be in a first pharmaceuticalcomposition that includes a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least one of the otheradditional agent(s) can be in a second pharmaceutical composition.

The dosing amount(s) and dosing schedule(s) when using a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition that includes a compound of Formula (I), or apharmaceutically acceptable salt thereof, and one or more additionalagents are within the knowledge of those skilled in the art. Forexample, when performing a conventional standard of care therapy usingart-recognized dosing amounts and dosing schedules, a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition that includes a compound of Formula (I), or apharmaceutically acceptable salt thereof, can be administered inaddition to that therapy, or in place of one of the agents of acombination therapy, using effective amounts and dosing protocols asdescribed herein.

The order of administration of a compound of Formula (I), or apharmaceutically acceptable salt thereof, with one or more additionalagent(s) can vary. In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can be administered prior toall additional agents. In other embodiments, a compound of Formula (I),or a pharmaceutically acceptable salt thereof, can be administered priorto at least one additional agent. In still other embodiments, a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, can beadministered concomitantly with one or more additional agent(s). In yetstill other embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can be administered subsequentto the administration of at least one additional agent. In someembodiments, a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, can be administered subsequent to the administration ofall additional agents.

In some embodiments, the combination of a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with one ormore additional agent(s) in FIGS. 1-8 (including pharmaceuticallyacceptable salts and prodrugs thereof) can result in an additive effect.In some embodiments, the combination of a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with one ormore additional agent(s) in FIGS. 1-8 (including pharmaceuticallyacceptable salts and prodrugs thereof) can result in a synergisticeffect. In some embodiments, the combination of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, in combination withone or more additional agent(s) in FIGS. 1-8 (including pharmaceuticallyacceptable salts and prodrugs thereof) can result in a stronglysynergistic effect. In some embodiments, the combination of a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, incombination with one or more additional agent(s) in FIGS. 1-8 (includingpharmaceutically acceptable salts and prodrugs thereof) is notantagonistic.

As used herein, the term “antagonistic” means that the activity of thecombination of compounds is less compared to the sum of the activitiesof the compounds in combination when the activity of each compound isdetermined individually (i.e. as a single compound). As used herein, theterm “synergistic effect” means that the activity of the combination ofcompounds is greater than the sum of the individual activities of thecompounds in the combination when the activity of each compound isdetermined individually. As used herein, the term “additive effect”means that the activity of the combination of compounds is about equalto the sum of the individual activities of the compound in thecombination when the activity of each compound is determinedindividually.

A potential advantage of utilizing a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with one ormore additional agent(s) in FIGS. 1-8 (including pharmaceuticallyacceptable salts thereof) may be a reduction in the required amount(s)of one or more compounds of FIGS. 1-8 (including pharmaceuticallyacceptable salts thereof) that is effective in treating a diseasecondition disclosed herein (for example, HCV), as compared to the amountrequired to achieve same therapeutic result when one or more compoundsof FIGS. 1-8 (including pharmaceutically acceptable salts thereof) areadministered without a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof. For example, the amount of a compound in FIGS.1-8 (including a pharmaceutically acceptable salt thereof), can be lesscompared to the amount of the compound in FIGS. 1-8 (including apharmaceutically acceptable salt thereof), needed to achieve the sameviral load reduction when administered as a monotherapy. Anotherpotential advantage of utilizing a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with one ormore additional agent(s) in FIGS. 1-8 (including pharmaceuticallyacceptable salts thereof) is that the use of two or more compoundshaving different mechanism of actions can create a higher barrier to thedevelopment of resistant viral strains compared to the barrier when acompound is administered as monotherapy.

Additional advantages of utilizing a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with one ormore additional agent(s) in FIGS. 1-8 (including pharmaceuticallyacceptable salts thereof) may include little to no cross resistancebetween a compound of Formula (I), or a pharmaceutically acceptable saltthereof, and one or more additional agent(s) in FIGS. 1-8 (includingpharmaceutically acceptable salts thereof) thereof; different routes forelimination of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and one or more additional agent(s) in FIGS.1-8 (including pharmaceutically acceptable salts thereof); little to nooverlapping toxicities between a compound of Formula (I), or apharmaceutically acceptable salt thereof, and one or more additionalagent(s) in FIGS. 1-8 (including pharmaceutically acceptable saltsthereof); little to no significant effects on cytochrome P450; little tono pharmacokinetic interactions between a compound of Formula (I), or apharmaceutically acceptable salt thereof, and one or more additionalagent(s) in FIGS. 1-8 (including pharmaceutically acceptable saltsthereof); greater percentage of subjects achieving a sustained viralresponse compared to when a compound is administered as monotherapyand/or a decrease in treatment time to achieve a sustained viralresponse compared to when a compound is administered as monotherapy.

A non-limiting list of example combination of compounds of Formula (I),or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition that includes a compound described herein, with one or moreadditional agent(s) are provided in Tables A, B, C, D and E. Eachnumbered X and Y compound in Tables A, B, C, D and E has a correspondingname and/or structure provided in FIGS. 1-8. The numbered compounds inTables A, B, C, D and E includes pharmaceutically acceptable salts ofthe compounds and pharmaceutical compositions containing the compoundsor a pharmaceutically acceptable salt thereof. For example, 1001includes the compound corresponding to 1001, pharmaceutically acceptablesalts thereof, and pharmaceutical compositions that include compound1001 and/or a pharmaceutically acceptable salt thereof. The combinationsexemplified in Tables A, B, C, D and E are designated by the formulaX:Y, which represents a combination of a compound X with a compound Y.For example, the combination designated as 1001:9004 in Table Arepresents a combination of compound 1001 with compound 9004, includingpharmaceutically acceptable salts of compound 1001 and/or 9004, andpharmaceutical compositions including compound 1001 and 9004 (includingpharmaceutical compositions that include pharmaceutically acceptablesalts of compound 1001 and/or compound 9004). Thus, the combinationdesignated as 1001:9004 in Table A represents the combination ofTelaprevir (compound 1001, as shown in FIG. 1) and

(compound 9004, as shown in FIG. 9), including pharmaceuticallyacceptable salts of compound 1001 and/or 9004, and pharmaceuticalcompositions including compound 1001 and 9004 (including pharmaceuticalcompositions that include pharmaceutically acceptable salts of compound1001 and/or compound 9004). Each of the combinations provided in TablesA, B, C, D and E can be used with one, two, three or more additionalagents described herein. In some embodiments described herein, thecombination of agents can be used to treat, ameliorate and/or inhibit avirus and/or a viral infection, wherein the virus can be HCV and theviral infection can be an HCV viral infection.

TABLE A Example combinations of a compound X with a compound Y. X:Y X:YX:Y X:Y X:Y X:Y 1001:9000 1001:9001 1001:9002 1001:9003 1001:90041001:9005 1002:9000 1002:9001 1002:9002 1002:9003 1002:9004 1002:90051003:9000 1003:9001 1003:9002 1003:9003 1003:9004 1003:9005 1004:90001004:9001 1004:9002 1004:9003 1004:9004 1004:9005 1005:9000 1005:90011005:9002 1005:9003 1005:9004 1005:9005 1006:9000 1006:9001 1006:90021006:9003 1006:9004 1006:9005 1007:9000 1007:9001 1007:9002 1007:90031007:9004 1007:9005 1008:9000 1008:9001 1008:9002 1008:9003 1008:90041008:9005 1009:9000 1009:9001 1009:9002 1009:9003 1009:9004 1009:90051010:9000 1010:9001 1010:9002 1010:9003 1010:9004 1010:9005 1011:90001011:9001 1011:9002 1011:9003 1011:9004 1011:9005 1012:9000 1012:90011012:9002 1012:9003 1012:9004 1012:9005 1013:9000 1013:9001 1013:90021013:9003 1013:9004 1013:9005 1014:9000 1014:9001 1014:9002 1014:90031014:9004 1014:9005 1015:9000 1015:9001 1015:9002 1015:9003 1015:90041015:9005 1016:9000 1016:9001 1016:9002 1016:9003 1016:9004 1016:90052001:9000 2001:9001 2001:9002 2001:9003 2001:9004 2001:9005 2002:90002002:9001 2002:9002 2002:9003 2002:9004 2002:9005 2003:9000 2003:90012003:9002 2003:9003 2003:9004 2003:9005 2004:9000 2004:9001 2004:90022004:9003 2004:9004 2004:9005 2005:9000 2005:9001 2005:9002 2005:90032005:9004 2005:9005 2006:9000 2006:9001 2006:9002 2006:9003 2006:90042006:9005 2007:9000 2007:9001 2007:9002 2007:9003 2007:9004 2007:90052008:9000 2008:9001 2008:9002 2008:9003 2008:9004 2008:9005 2009:90002009:9001 2009:9002 2009:9003 2009:9004 2009:9005 2010:9000 2010:90012010:9002 2010:9003 2010:9004 2010:9005 2011:9000 2011:9001 2011:90022011:9003 2011:9004 2011:9005 2012:9000 2012:9001 2012:9002 2012:90032012:9004 2012:9005 1001:9006 1001:9007 1001:9008 1001:9009 1001:90101001:9011 1002:9006 1002:9007 1002:9008 1002:9009 1002:9010 1002:90111003:9006 1003:9007 1003:9008 1003:9009 1003:9010 1003:9011 1004:90061004:9007 1004:9008 1004:9009 1004:9010 1004:9011 1005:9006 1005:90071005:9008 1005:9009 1005:9010 1005:9011 1006:9006 1006:9007 1006:90081006:9009 1006:9010 1006:9011 1007:9006 1007:9007 1007:9008 1007:90091007:9010 1007:9011 1008:9006 1008:9007 1008:9008 1008:9009 1008:90101008:9011 1009:9006 1009:9007 1009:9008 1009:9009 1009:9010 1009:90111010:9006 1010:9007 1010:9008 1010:9009 1010:9010 1010:9011 1011:90061011:9007 1011:9008 1011:9009 1011:9010 1011:9011 1012:9006 1012:90071012:9008 1012:9009 1012:9010 1012:9011 1013:9006 1013:9007 1013:90081013:9009 1013:9010 1013:9011 1014:9006 1014:9007 1014:9008 1014:90091014:9010 1014:9011 1015:9006 1015:9007 1015:9008 1015:9009 1015:90101015:9011 1016:9006 1016:9007 1016:9008 1016:9009 1016:9010 1016:90112001:9006 2001:9007 2001:9008 2001:9009 2001:9010 2001:9011 2002:90062002:9007 2002:9008 2002:9009 2002:9010 2002:9011 2003:9006 2003:90072003:9008 2003:9009 2003:9010 2003:9011 2004:9006 2004:9007 2004:90082004:9009 2004:9010 2004:9011 2005:9006 2005:9007 2005:9008 2005:90092005:9010 2005:9011 2006:9006 2006:9007 2006:9008 2006:9009 2006:90102006:9011 2007:9006 2007:9007 2007:9008 2007:9009 2007:9010 2007:90112008:9006 2008:9007 2008:9008 2008:9009 2008:9010 2008:9011 2009:90062009:9007 2009:9008 2009:9009 2009:9010 2009:9011 2010:9006 2010:90072010:9008 2010:9009 2010:9010 2010:9011 2011:9006 2011:9007 2011:90082011:9009 2011:9010 2011:9011 2012:9006 2012:9007 2012:9008 2012:90092012:9010 2012:9011 1001:9012 1001:9013 1001:9014 1001:9015 1001:90161001:9017 1002:9012 1002:9013 1002:9014 1002:9015 1002:9016 1002:90171003:9012 1003:9013 1003:9014 1003:9015 1003:9016 1003:9017 1004:90121004:9013 1004:9014 1004:9015 1004:9016 1004:9017 1005:9012 1005:90131005:9014 1005:9015 1005:9016 1005:9017 1006:9012 1006:9013 1006:90141006:9015 1006:9016 1006:9017 1007:9012 1007:9013 1007:9014 1007:90151007:9016 1007:9017 1008:9012 1008:9013 1008:9014 1008:9015 1008:90161008:9017 1009:9012 1009:9013 1009:9014 1009:9015 1009:9016 1009:90171010:9012 1010:9013 1010:9014 1010:9015 1010:9016 1010:9017 1011:90121011:9013 1011:9014 1011:9015 1011:9016 1011:9017 1012:9012 1012:90131012:9014 1012:9015 1012:9016 1012:9017 1013:9012 1013:9013 1013:90141013:9015 1013:9016 1013:9017 1014:9012 1014:9013 1014:9014 1014:90151014:9016 1014:9017 1015:9012 1015:9013 1015:9014 1015:9015 1015:90161015:9017 1016:9012 1016:9013 1016:9014 1016:9015 1016:9016 1016:90172001:9012 2001:9013 2001:9014 2001:9015 2001:9016 2001:9017 2002:90122002:9013 2002:9014 2002:9015 2002:9016 2002:9017 2003:9012 2003:90132003:9014 2003:9015 2003:9016 2003:9017 2004:9012 2004:9013 2004:90142004:9015 2004:9016 2004:9017 2005:9012 2005:9013 2005:9014 2005:90152005:9016 2005:9017 2006:9012 2006:9013 2006:9014 2006:9015 2006:90162006:9017 2007:9012 2007:9013 2007:9014 2007:9015 2007:9016 2007:90172008:9012 2008:9013 2008:9014 2008:9015 2008:9016 2008:9017 2009:90122009:9013 2009:9014 2009:9015 2009:9016 2009:9017 2010:9012 2010:90132010:9014 2010:9015 2010:9016 2010:9017 2011:9012 2011:9013 2011:90142011:9015 2011:9016 2011:9017 2012:9012 2012:9013 2012:9014 2012:90152012:9016 2012:9017 1001:9018 1001:9019 1001:9020 1001:9021 1001:90221001:9023 1002:9018 1002:9019 1002:9020 1002:9021 1002:9022 1002:90231003:9018 1003:9019 1003:9020 1003:9021 1003:9022 1003:9023 1004:90181004:9019 1004:9020 1004:9021 1004:9022 1004:9023 1005:9018 1005:90191005:9020 1005:9021 1005:9022 1005:9023 1006:9018 1006:9019 1006:90201006:9021 1006:9022 1006:9023 1007:9018 1007:9019 1007:9020 1007:90211007:9022 1007:9023 1008:9018 1008:9019 1008:9020 1008:9021 1008:90221008:9023 1009:9018 1009:9019 1009:9020 1009:9021 1009:9022 1009:90231010:9018 1010:9019 1010:9020 1010:9021 1010:9022 1010:9023 1011:90181011:9019 1011:9020 1011:9021 1011:9022 1011:9023 1012:9018 1012:90191012:9020 1012:9021 1012:9022 1012:9023 1013:9018 1013:9019 1013:90201013:9021 1013:9022 1013:9023 1014:9018 1014:9019 1014:9020 1014:90211014:9022 1014:9023 1015:9018 1015:9019 1015:9020 1015:9021 1015:90221015:9023 1016:9018 1016:9019 1016:9020 1016:9021 1016:9022 1016:90232001:9018 2001:9019 2001:9020 2001:9021 2001:9022 2001:9023 2002:90182002:9019 2002:9020 2002:9021 2002:9022 2002:9023 2003:9018 2003:90192003:9020 2003:9021 2003:9022 2003:9023 2004:9018 2004:9019 2004:90202004:9021 2004:9022 2004:9023 2005:9018 2005:9019 2005:9020 2005:90212005:9022 2005:9023 2006:9018 2006:9019 2006:9020 2006:9021 2006:90222006:9023 2007:9018 2007:9019 2007:9020 2007:9021 2007:9022 2007:90232008:9018 2008:9019 2008:9020 2008:9021 2008:9022 2008:9023 2009:90182009:9019 2009:9020 2009:9021 2009:9022 2009:9023 2010:9018 2010:90192010:9020 2010:9021 2010:9022 2010:9023 2011:9018 2011:9019 2011:90202011:9021 2011:9022 2011:9023 2012:9018 2012:9019 2012:9020 2012:90212012:9022 2012:9023 1001:9024 1001:9025 1001:9026 1001:9027 1001:90281001:9029 1002:9024 1002:9025 1002:9026 1002:9027 1002:9028 1002:90291003:9024 1003:9025 1003:9026 1003:9027 1003:9028 1003:9029 1004:90241004:9025 1004:9026 1004:9027 1004:9028 1004:9029 1005:9024 1005:90251005:9026 1005:9027 1005:9028 1005:9029 1006:9024 1006:9025 1006:90261006:9027 1006:9028 1006:9029 1007:9024 1007:9025 1007:9026 1007:90271007:9028 1007:9029 1008:9024 1008:9025 1008:9026 1008:9027 1008:90281008:9029 1009:9024 1009:9025 1009:9026 1009:9027 1009:9028 1009:90291010:9024 1010:9025 1010:9026 1010:9027 1010:9028 1010:9029 1011:90241011:9025 1011:9026 1011:9027 1011:9028 1011:9029 1012:9024 1012:90251012:9026 1012:9027 1012:9028 1012:9029 1013:9024 1013:9025 1013:90261013:9027 1013:9028 1013:9029 1014:9024 1014:9025 1014:9026 1014:90271014:9028 1014:9029 1015:9024 1015:9025 1015:9026 1015:9027 1015:90281015:9029 1016:9024 1016:9025 1016:9026 1016:9027 1016:9028 1016:90292001:9024 2001:9025 2001:9026 2001:9027 2001:9028 2001:9029 2002:90242002:9025 2002:9026 2002:9027 2002:9028 2002:9029 2003:9024 2003:90252003:9026 2003:9027 2003:9028 2003:9029 2004:9024 2004:9025 2004:90262004:9027 2004:9028 2004:9029 2005:9024 2005:9025 2005:9026 2005:90272005:9028 2005:9029 2006:9024 2006:9025 2006:9026 2006:9027 2006:90282006:9029 2007:9024 2007:9025 2007:9026 2007:9027 2007:9028 2007:90292008:9024 2008:9025 2008:9026 2008:9027 2008:9028 2008:9029 2009:90242009:9025 2009:9026 2009:9027 2009:9028 2009:9029 2010:9024 2010:90252010:9026 2010:9027 2010:9028 2010:9029 2011:9024 2011:9025 2011:90262011:9027 2011:9028 2011:9029 2012:9024 2012:9025 2012:9026 2012:90272012:9028 2012:9029 1001:9030 1001:9031 1001:9032 1001:9033 1001:90341001:9035 1002:9030 1002:9031 1002:9032 1002:9033 1002:9034 1002:90351003:9030 1003:9031 1003:9032 1003:9033 1003:9034 1003:9035 1004:90301004:9031 1004:9032 1004:9033 1004:9034 1004:9035 1005:9030 1005:90311005:9032 1005:9033 1005:9034 1005:9035 1006:9030 1006:9031 1006:90321006:9033 1006:9034 1006:9035 1007:9030 1007:9031 1007:9032 1007:90331007:9034 1007:9035 1008:9030 1008:9031 1008:9032 1008:9033 1008:90341008:9035 1009:9030 1009:9031 1009:9032 1009:9033 1009:9034 1009:90351010:9030 1010:9031 1010:9032 1010:9033 1010:9034 1010:9035 1011:90301011:9031 1011:9032 1011:9033 1011:9034 1011:9035 1012:9030 1012:90311012:9032 1012:9033 1012:9034 1012:9035 1013:9030 1013:9031 1013:90321013:9033 1013:9034 1013:9035 1014:9030 1014:9031 1014:9032 1014:90331014:9034 1014:9035 1015:9030 1015:9031 1015:9032 1015:9033 1015:90341015:9035 1016:9030 1016:9031 1016:9032 1016:9033 1016:9034 1016:90352001:9030 2001:9031 2001:9032 2001:9033 2001:9034 2001:9035 2002:90302002:9031 2002:9032 2002:9033 2002:9034 2002:9035 2003:9030 2003:90312003:9032 2003:9033 2003:9034 2003:9035 2004:9030 2004:9031 2004:90322004:9033 2004:9034 2004:9035 2005:9030 2005:9031 2005:9032 2005:90332005:9034 2005:9035 2006:9030 2006:9031 2006:9032 2006:9033 2006:90342006:9035 2007:9030 2007:9031 2007:9032 2007:9033 2007:9034 2007:90352008:9030 2008:9031 2008:9032 2008:9033 2008:9034 2008:9035 2009:90302009:9031 2009:9032 2009:9033 2009:9034 2009:9035 2010:9030 2010:90312010:9032 2010:9033 2010:9034 2010:9035 2011:9030 2011:9031 2011:90322011:9033 2011:9034 2011:9035 2012:9030 2012:9031 2012:9032 2012:90332012:9034 2012:9035 1001:9036 1001:9037 1001:9038 1001:9039 1001:90401001:9041 1002:9036 1002:9037 1002:9038 1002:9039 1002:9040 1002:90411003:9036 1003:9037 1003:9038 1003:9039 1003:9040 1003:9041 1004:90361004:9037 1004:9038 1004:9039 1004:9040 1004:9041 1005:9036 1005:90371005:9038 1005:9039 1005:9040 1005:9041 1006:9036 1006:9037 1006:90381006:9039 1006:9040 1006:9041 1007:9036 1007:9037 1007:9038 1007:90391007:9040 1007:9041 1008:9036 1008:9037 1008:9038 1008:9039 1008:90401008:9041 1009:9036 1009:9037 1009:9038 1009:9039 1009:9040 1009:90411010:9036 1010:9037 1010:9038 1010:9039 1010:9040 1010:9041 1011:90361011:9037 1011:9038 1011:9039 1011:9040 1011:9041 1012:9036 1012:90371012:9038 1012:9039 1012:9040 1012:9041 1013:9036 1013:9037 1013:90381013:9039 1013:9040 1013:9041 1014:9036 1014:9037 1014:9038 1014:90391014:9040 1014:9041 1015:9036 1015:9037 1015:9038 1015:9039 1015:90401015:9041 1016:9036 1016:9037 1016:9038 1016:9039 1016:9040 1016:90412001:9036 2001:9037 2001:9038 2001:9039 2001:9040 2001:9041 2002:90362002:9037 2002:9038 2002:9039 2002:9040 2002:9041 2003:9036 2003:90372003:9038 2003:9039 2003:9040 2003:9041 2004:9036 2004:9037 2004:90382004:9039 2004:9040 2004:9041 2005:9036 2005:9037 2005:9038 2005:90392005:9040 2005:9041 2006:9036 2006:9037 2006:9038 2006:9039 2006:90402006:9041 2007:9036 2007:9037 2007:9038 2007:9039 2007:9040 2007:90412008:9036 2008:9037 2008:9038 2008:9039 2008:9040 2008:9041 2009:90362009:9037 2009:9038 2009:9039 2009:9040 2009:9041 2010:9036 2010:90372010:9038 2010:9039 2010:9040 2010:9041 2011:9036 2011:9037 2011:90382011:9039 2011:9040 2011:9041 2012:9036 2012:9037 2012:9038 2012:90392012:9040 2012:9041 1001:9042 1001:9043 1001:9044 1001:9045 1001:90461001:9047 1002:9042 1002:9043 1002:9044 1002:9045 1002:9046 1002:90471003:9042 1003:9043 1003:9044 1003:9045 1003:9046 1003:9047 1004:90421004:9043 1004:9044 1004:9045 1004:9046 1004:9047 1005:9042 1005:90431005:9044 1005:9045 1005:9046 1005:9047 1006:9042 1006:9043 1006:90441006:9045 1006:9046 1006:9047 1007:9042 1007:9043 1007:9044 1007:90451007:9046 1007:9047 1008:9042 1008:9043 1008:9044 1008:9045 1008:90461008:9047 1009:9042 1009:9043 1009:9044 1009:9045 1009:9046 1009:90471010:9042 1010:9043 1010:9044 1010:9045 1010:9046 1010:9047 1011:90421011:9043 1011:9044 1011:9045 1011:9046 1011:9047 1012:9042 1012:90431012:9044 1012:9045 1012:9046 1012:9047 1013:9042 1013:9043 1013:90441013:9045 1013:9046 1013:9047 1014:9042 1014:9043 1014:9044 1014:90451014:9046 1014:9047 1015:9042 1015:9043 1015:9044 1015:9045 1015:90461015:9047 1016:9042 1016:9043 1016:9044 1016:9045 1016:9046 1016:90472001:9042 2001:9043 2001:9044 2001:9045 2001:9046 2001:9047 2002:90422002:9043 2002:9044 2002:9045 2002:9046 2002:9047 2003:9042 2003:90432003:9044 2003:9045 2003:9046 2003:9047 2004:9042 2004:9043 2004:90442004:9045 2004:9046 2004:9047 2005:9042 2005:9043 2005:9044 2005:90452005:9046 2005:9047 2006:9042 2006:9043 2006:9044 2006:9045 2006:90462006:9047 2007:9042 2007:9043 2007:9044 2007:9045 2007:9046 2007:90472008:9042 2008:9043 2008:9044 2008:9045 2008:9046 2008:9047 2009:90422009:9043 2009:9044 2009:9045 2009:9046 2009:9047 2010:9042 2010:90432010:9044 2010:9045 2010:9046 2010:9047 2011:9042 2011:9043 2011:90442011:9045 2011:9046 2011:9047 2012:9042 2012:9043 2012:9044 2012:90452012:9046 2012:9047 1001:9048 1001:9049 1001:9050 1001:9051 1001:90521001:9053 1002:9048 1002:9049 1002:9050 1002:9051 1002:9052 1002:90531003:9048 1003:9049 1003:9050 1003:9051 1003:9052 1003:9053 1004:90481004:9049 1004:9050 1004:9051 1004:9052 1004:9053 1005:9048 1005:90491005:9050 1005:9051 1005:9052 1005:9053 1006:9048 1006:9049 1006:90501006:9051 1006:9052 1006:9053 1007:9048 1007:9049 1007:9050 1007:90511007:9052 1007:9053 1008:9048 1008:9049 1008:9050 1008:9051 1008:90521008:9053 1009:9048 1009:9049 1009:9050 1009:9051 1009:9052 1009:90531010:9048 1010:9049 1010:9050 1010:9051 1010:9052 1010:9053 1011:90481011:9049 1011:9050 1011:9051 1011:9052 1011:9053 1012:9048 1012:90491012:9050 1012:9051 1012:9052 1012:9053 1013:9048 1013:9049 1013:90501013:9051 1013:9052 1013:9053 1014:9048 1014:9049 1014:9050 1014:90511014:9052 1014:9053 1015:9048 1015:9049 1015:9050 1015:9051 1015:90521015:9053 1016:9048 1016:9049 1016:9050 1016:9051 1016:9052 1016:90532001:9048 2001:9049 2001:9050 2001:9051 2001:9052 2001:9053 2002:90482002:9049 2002:9050 2002:9051 2002:9052 2002:9053 2003:9048 2003:90492003:9050 2003:9051 2003:9052 2003:9053 2004:9048 2004:9049 2004:90502004:9051 2004:9052 2004:9053 2005:9048 2005:9049 2005:9050 2005:90512005:9052 2005:9053 2006:9048 2006:9049 2006:9050 2006:9051 2006:90522006:9053 2007:9048 2007:9049 2007:9050 2007:9051 2007:9052 2007:90532008:9048 2008:9049 2008:9050 2008:9051 2008:9052 2008:9053 2009:90482009:9049 2009:9050 2009:9051 2009:9052 2009:9053 2010:9048 2010:90492010:9050 2010:9051 2010:9052 2010:9053 2011:9048 2011:9049 2011:90502011:9051 2011:9052 2011:9053 2012:9048 2012:9049 2012:9050 2012:90512012:9052 2012:9053 1001:9054 1001:9055 1001:9056 1001:9057 1001:90581001:9059 1002:9054 1002:9055 1002:9056 1002:9057 1002:9058 1002:90591003:9054 1003:9055 1003:9056 1003:9057 1003:9058 1003:9059 1004:90541004:9055 1004:9056 1004:9057 1004:9058 1004:9059 1005:9054 1005:90551005:9056 1005:9057 1005:9058 1005:9059 1006:9054 1006:9055 1006:90561006:9057 1006:9058 1006:9059 1007:9054 1007:9055 1007:9056 1007:90571007:9058 1007:9059 1008:9054 1008:9055 1008:9056 1008:9057 1008:90581008:9059 1009:9054 1009:9055 1009:9056 1009:9057 1009:9058 1009:90591010:9054 1010:9055 1010:9056 1010:9057 1010:9058 1010:9059 1011:90541011:9055 1011:9056 1011:9057 1011:9058 1011:9059 1012:9054 1012:90551012:9056 1012:9057 1012:9058 1012:9059 1013:9054 1013:9055 1013:90561013:9057 1013:9058 1013:9059 1014:9054 1014:9055 1014:9056 1014:90571014:9058 1014:9059 1015:9054 1015:9055 1015:9056 1015:9057 1015:90581015:9059 1016:9054 1016:9055 1016:9056 1016:9057 1016:9058 1016:90592001:9054 2001:9055 2001:9056 2001:9057 2001:9058 2001:9059 2002:90542002:9055 2002:9056 2002:9057 2002:9058 2002:9059 2003:9054 2003:90552003:9056 2003:9057 2003:9058 2003:9059 2004:9054 2004:9055 2004:90562004:9057 2004:9058 2004:9059 2005:9054 2005:9055 2005:9056 2005:90572005:9058 2005:9059 2006:9054 2006:9055 2006:9056 2006:9057 2006:90582006:9059 2007:9054 2007:9055 2007:9056 2007:9057 2007:9058 2007:90592008:9054 2008:9055 2008:9056 2008:9057 2008:9058 2008:9059 2009:90542009:9055 2009:9056 2009:9057 2009:9058 2009:9059 2010:9054 2010:90552010:9056 2010:9057 2010:9058 2010:9059 2011:9054 2011:9055 2011:90562011:9057 2011:9058 2011:9059 2012:9054 2012:9055 2012:9056 2012:90572012:9058 2012:9059 1001:9060 1001:9061 1001:9062 1001:9063 1001:90641001:9065 1002:9060 1002:9061 1002:9062 1002:9063 1002:9064 1002:90651003:9060 1003:9061 1003:9062 1003:9063 1003:9064 1003:9065 1004:90601004:9061 1004:9062 1004:9063 1004:9064 1004:9065 1005:9060 1005:90611005:9062 1005:9063 1005:9064 1005:9065 1006:9060 1006:9061 1006:90621006:9063 1006:9064 1006:9065 1007:9060 1007:9061 1007:9062 1007:90631007:9064 1007:9065 1008:9060 1008:9061 1008:9062 1008:9063 1008:90641008:9065 1009:9060 1009:9061 1009:9062 1009:9063 1009:9064 1009:90651010:9060 1010:9061 1010:9062 1010:9063 1010:9064 1010:9065 1011:90601011:9061 1011:9062 1011:9063 1011:9064 1011:9065 1012:9060 1012:90611012:9062 1012:9063 1012:9064 1012:9065 1013:9060 1013:9061 1013:90621013:9063 1013:9064 1013:9065 1014:9060 1014:9061 1014:9062 1014:90631014:9064 1014:9065 1015:9060 1015:9061 1015:9062 1015:9063 1015:90641015:9065 1016:9060 1016:9061 1016:9062 1016:9063 1016:9064 1016:90652001:9060 2001:9061 2001:9062 2001:9063 2001:9064 2001:9065 2002:90602002:9061 2002:9062 2002:9063 2002:9064 2002:9065 2003:9060 2003:90612003:9062 2003:9063 2003:9064 2003:9065 2004:9060 2004:9061 2004:90622004:9063 2004:9064 2004:9065 2005:9060 2005:9061 2005:9062 2005:90632005:9064 2005:9065 2006:9060 2006:9061 2006:9062 2006:9063 2006:90642006:9065 2007:9060 2007:9061 2007:9062 2007:9063 2007:9064 2007:90652008:9060 2008:9061 2008:9062 2008:9063 2008:9064 2008:9065 2009:90602009:9061 2009:9062 2009:9063 2009:9064 2009:9065 2010:9060 2010:90612010:9062 2010:9063 2010:9064 2010:9065 2011:9060 2011:9061 2011:90622011:9063 2011:9064 2011:9065 2012:9060 2012:9061 2012:9062 2012:90632012:9064 2012:9065 1001:9066 1001:9067 1001:9068 1001:9069 1001:90701001:9071 1002:9066 1002:9067 1002:9068 1002:9069 1002:9070 1002:90711003:9066 1003:9067 1003:9068 1003:9069 1003:9070 1003:9071 1004:90661004:9067 1004:9068 1004:9069 1004:9070 1004:9071 1005:9066 1005:90671005:9068 1005:9069 1005:9070 1005:9071 1006:9066 1006:9067 1006:90681006:9069 1006:9070 1006:9071 1007:9066 1007:9067 1007:9068 1007:90691007:9070 1007:9071 1008:9066 1008:9067 1008:9068 1008:9069 1008:90701008:9071 1009:9066 1009:9067 1009:9068 1009:9069 1009:9070 1009:90711010:9066 1010:9067 1010:9068 1010:9069 1010:9070 1010:9071 1011:90661011:9067 1011:9068 1011:9069 1011:9070 1011:9071 1012:9066 1012:90671012:9068 1012:9069 1012:9070 1012:9071 1013:9066 1013:9067 1013:90681013:9069 1013:9070 1013:9071 1014:9066 1014:9067 1014:9068 1014:90691014:9070 1014:9071 1015:9066 1015:9067 1015:9068 1015:9069 1015:90701015:9071 1016:9066 1016:9067 1016:9068 1016:9069 1016:9070 1016:90712001:9066 2001:9067 2001:9068 2001:9069 2001:9070 2001:9071 2002:90662002:9067 2002:9068 2002:9069 2002:9070 2002:9071 2003:9066 2003:90672003:9068 2003:9069 2003:9070 2003:9071 2004:9066 2004:9067 2004:90682004:9069 2004:9070 2004:9071 2005:9066 2005:9067 2005:9068 2005:90692005:9070 2005:9071 2006:9066 2006:9067 2006:9068 2006:9069 2006:90702006:9071 2007:9066 2007:9067 2007:9068 2007:9069 2007:9070 2007:90712008:9066 2008:9067 2008:9068 2008:9069 2008:9070 2008:9071 2009:90662009:9067 2009:9068 2009:9069 2009:9070 2009:9071 2010:9066 2010:90672010:9068 2010:9069 2010:9070 2010:9071 2011:9066 2011:9067 2011:90682011:9069 2011:9070 2011:9071 2012:9066 2012:9067 2012:9068 2012:90692012:9070 2012:9071 1001:9072 1001:9073 1001:9074 1001:9075 1001:90761001:9077 1002:9072 1002:9073 1002:9074 1002:9075 1002:9076 1002:90771003:9072 1003:9073 1003:9074 1003:9075 1003:9076 1003:9077 1004:90721004:9073 1004:9074 1004:9075 1004:9076 1004:9077 1005:9072 1005:90731005:9074 1005:9075 1005:9076 1005:9077 1006:9072 1006:9073 1006:90741006:9075 1006:9076 1006:9077 1007:9072 1007:9073 1007:9074 1007:90751007:9076 1007:9077 1008:9072 1008:9073 1008:9074 1008:9075 1008:90761008:9077 1009:9072 1009:9073 1009:9074 1009:9075 1009:9076 1009:90771010:9072 1010:9073 1010:9074 1010:9075 1010:9076 1010:9077 1011:90721011:9073 1011:9074 1011:9075 1011:9076 1011:9077 1012:9072 1012:90731012:9074 1012:9075 1012:9076 1012:9077 1013:9072 1013:9073 1013:90741013:9075 1013:9076 1013:9077 1014:9072 1014:9073 1014:9074 1014:90751014:9076 1014:9077 1015:9072 1015:9073 1015:9074 1015:9075 1015:90761015:9077 1016:9072 1016:9073 1016:9074 1016:9075 1016:9076 1016:90772001:9072 2001:9073 2001:9074 2001:9075 2001:9076 2001:9077 2002:90722002:9073 2002:9074 2002:9075 2002:9076 2002:9077 2003:9072 2003:90732003:9074 2003:9075 2003:9076 2003:9077 2004:9072 2004:9073 2004:90742004:9075 2004:9076 2004:9077 2005:9072 2005:9073 2005:9074 2005:90752005:9076 2005:9077 2006:9072 2006:9073 2006:9074 2006:9075 2006:90762006:9077 2007:9072 2007:9073 2007:9074 2007:9075 2007:9076 2007:90772008:9072 2008:9073 2008:9074 2008:9075 2008:9076 2008:9077 2009:90722009:9073 2009:9074 2009:9075 2009:9076 2009:9077 2010:9072 2010:90732010:9074 2010:9075 2010:9076 2010:9077 2011:9072 2011:9073 2011:90742011:9075 2011:9076 2011:9077 2012:9072 2012:9073 2012:9074 2012:90752012:9076 2012:9077 1001:9078 1001:9079 1001:9080 1001:9081 1001:90821001:9083 1002:9078 1002:9079 1002:9080 1002:9081 1002:9082 1002:90831003:9078 1003:9079 1003:9080 1003:9081 1003:9082 1003:9083 1004:90781004:9079 1004:9080 1004:9081 1004:9082 1004:9083 1005:9078 1005:90791005:9080 1005:9081 1005:9082 1005:9083 1006:9078 1006:9079 1006:90801006:9081 1006:9082 1006:9083 1007:9078 1007:9079 1007:9080 1007:90811007:9082 1007:9083 1008:9078 1008:9079 1008:9080 1008:9081 1008:90821008:9083 1009:9078 1009:9079 1009:9080 1009:9081 1009:9082 1009:90831010:9078 1010:9079 1010:9080 1010:9081 1010:9082 1010:9083 1011:90781011:9079 1011:9080 1011:9081 1011:9082 1011:9083 1012:9078 1012:90791012:9080 1012:9081 1012:9082 1012:9083 1013:9078 1013:9079 1013:90801013:9081 1013:9082 1013:9083 1014:9078 1014:9079 1014:9080 1014:90811014:9082 1014:9083 1015:9078 1015:9079 1015:9080 1015:9081 1015:90821015:9083 1016:9078 1016:9079 1016:9080 1016:9081 1016:9082 1016:90832001:9078 2001:9079 2001:9080 2001:9081 2001:9082 2001:9083 2002:90782002:9079 2002:9080 2002:9081 2002:9082 2002:9083 2003:9078 2003:90792003:9080 2003:9081 2003:9082 2003:9083 2004:9078 2004:9079 2004:90802004:9081 2004:9082 2004:9083 2005:9078 2005:9079 2005:9080 2005:90812005:9082 2005:9083 2006:9078 2006:9079 2006:9080 2006:9081 2006:90822006:9083 2007:9078 2007:9079 2007:9080 2007:9081 2007:9082 2007:90832008:9078 2008:9079 2008:9080 2008:9081 2008:9082 2008:9083 2009:90782009:9079 2009:9080 2009:9081 2009:9082 2009:9083 2010:9078 2010:90792010:9080 2010:9081 2010:9082 2010:9083 2011:9078 2011:9079 2011:90802011:9081 2011:9082 2011:9083 2012:9078 2012:9079 2012:9080 2012:90812012:9082 2012:9083 1001:9084 1001:9085 1001:9086 1001:9087 1001:90881001:9089 1002:9084 1002:9085 1002:9086 1002:9087 1002:9088 1002:90891003:9084 1003:9085 1003:9086 1003:9087 1003:9088 1003:9089 1004:90841004:9085 1004:9086 1004:9087 1004:9088 1004:9089 1005:9084 1005:90851005:9086 1005:9087 1005:9088 1005:9089 1006:9084 1006:9085 1006:90861006:9087 1006:9088 1006:9089 1007:9084 1007:9085 1007:9086 1007:90871007:9088 1007:9089 1008:9084 1008:9085 1008:9086 1008:9087 1008:90881008:9089 1009:9084 1009:9085 1009:9086 1009:9087 1009:9088 1009:90891010:9084 1010:9085 1010:9086 1010:9087 1010:9088 1010:9089 1011:90841011:9085 1011:9086 1011:9087 1011:9088 1011:9089 1012:9084 1012:90851012:9086 1012:9087 1012:9088 1012:9089 1013:9084 1013:9085 1013:90861013:9087 1013:9088 1013:9089 1014:9084 1014:9085 1014:9086 1014:90871014:9088 1014:9089 1015:9084 1015:9085 1015:9086 1015:9087 1015:90881015:9089 1016:9084 1016:9085 1016:9086 1016:9087 1016:9088 1016:90892001:9084 2001:9085 2001:9086 2001:9087 2001:9088 2001:9089 2002:90842002:9085 2002:9086 2002:9087 2002:9088 2002:9089 2003:9084 2003:90852003:9086 2003:9087 2003:9088 2003:9089 2004:9084 2004:9085 2004:90862004:9087 2004:9088 2004:9089 2005:9084 2005:9085 2005:9086 2005:90872005:9088 2005:9089 2006:9084 2006:9085 2006:9086 2006:9087 2006:90882006:9089 2007:9084 2007:9085 2007:9086 2007:9087 2007:9088 2007:90892008:9084 2008:9085 2008:9086 2008:9087 2008:9088 2008:9089 2009:90842009:9085 2009:9086 2009:9087 2009:9088 2009:9089 2010:9084 2010:90852010:9086 2010:9087 2010:9088 2010:9089 2011:9084 2011:9085 2011:90862011:9087 2011:9088 2011:9089 2012:9084 2012:9085 2012:9086 2012:90872012:9088 2012:9089 1001:9090 1001:9091 1001:9092 1001:9093 1001:90941001:9095 1002:9090 1002:9091 1002:9092 1002:9093 1002:9094 1002:90951003:9090 1003:9091 1003:9092 1003:9093 1003:9094 1003:9095 1004:90901004:9091 1004:9092 1004:9093 1004:9094 1004:9095 1005:9090 1005:90911005:9092 1005:9093 1005:9094 1005:9095 1006:9090 1006:9091 1006:90921006:9093 1006:9094 1006:9095 1007:9090 1007:9091 1007:9092 1007:90931007:9094 1007:9095 1008:9090 1008:9091 1008:9092 1008:9093 1008:90941008:9095 1009:9090 1009:9091 1009:9092 1009:9093 1009:9094 1009:90951010:9090 1010:9091 1010:9092 1010:9093 1010:9094 1010:9095 1011:90901011:9091 1011:9092 1011:9093 1011:9094 1011:9095 1012:9090 1012:90911012:9092 1012:9093 1012:9094 1012:9095 1013:9090 1013:9091 1013:90921013:9093 1013:9094 1013:9095 1014:9090 1014:9091 1014:9092 1014:90931014:9094 1014:9095 1015:9090 1015:9091 1015:9092 1015:9093 1015:90941015:9095 1016:9090 1016:9091 1016:9092 1016:9093 1016:9094 1016:90952001:9090 2001:9091 2001:9092 2001:9093 2001:9094 2001:9095 2002:90902002:9091 2002:9092 2002:9093 2002:9094 2002:9095 2003:9090 2003:90912003:9092 2003:9093 2003:9094 2003:9095 2004:9090 2004:9091 2004:90922004:9093 2004:9094 2004:9095 2005:9090 2005:9091 2005:9092 2005:90932005:9094 2005:9095 2006:9090 2006:9091 2006:9092 2006:9093 2006:90942006:9095 2007:9090 2007:9091 2007:9092 2007:9093 2007:9094 2007:90952008:9090 2008:9091 2008:9092 2008:9093 2008:9094 2008:9095 2009:90902009:9091 2009:9092 2009:9093 2009:9094 2009:9095 2010:9090 2010:90912010:9092 2010:9093 2010:9094 2010:9095 2011:9090 2011:9091 2011:90922011:9093 2011:9094 2011:9095 2012:9090 2012:9091 2012:9092 2012:90932012:9094 2012:9095 1001:9096 1001:9097 1001:9098 1001:9099 1001:91001001:9101 1002:9096 1002:9097 1002:9098 1002:9099 1002:9100 1002:91011003:9096 1003:9097 1003:9098 1003:9099 1003:9100 1003:9101 1004:90961004:9097 1004:9098 1004:9099 1004:9100 1004:9101 1005:9096 1005:90971005:9098 1005:9099 1005:9100 1005:9101 1006:9096 1006:9097 1006:90981006:9099 1006:9100 1006:9101 1007:9096 1007:9097 1007:9098 1007:90991007:9100 1007:9101 1008:9096 1008:9097 1008:9098 1008:9099 1008:91001008:9101 1009:9096 1009:9097 1009:9098 1009:9099 1009:9100 1009:91011010:9096 1010:9097 1010:9098 1010:9099 1010:9100 1010:9101 1011:90961011:9097 1011:9098 1011:9099 1011:9100 1011:9101 1012:9096 1012:90971012:9098 1012:9099 1012:9100 1012:9101 1013:9096 1013:9097 1013:90981013:9099 1013:9100 1013:9101 1014:9096 1014:9097 1014:9098 1014:90991014:9100 1014:9101 1015:9096 1015:9097 1015:9098 1015:9099 1015:91001015:9101 1016:9096 1016:9097 1016:9098 1016:9099 1016:9100 1016:91012001:9096 2001:9097 2001:9098 2001:9099 2001:9100 2001:9101 2002:90962002:9097 2002:9098 2002:9099 2002:9100 2002:9101 2003:9096 2003:90972003:9098 2003:9099 2003:9100 2003:9101 2004:9096 2004:9097 2004:90982004:9099 2004:9100 2004:9101 2005:9096 2005:9097 2005:9098 2005:90992005:9100 2005:9101 2006:9096 2006:9097 2006:9098 2006:9099 2006:91002006:9101 2007:9096 2007:9097 2007:9098 2007:9099 2007:9100 2007:91012008:9096 2008:9097 2008:9098 2008:9099 2008:9100 2008:9101 2009:90962009:9097 2009:9098 2009:9099 2009:9100 2009:9101 2010:9096 2010:90972010:9098 2010:9099 2010:9100 2010:9101 2011:9096 2011:9097 2011:90982011:9099 2011:9100 2011:9101 2012:9096 2012:9097 2012:9098 2012:90992012:9100 2012:9101 1001:9102 1001:9103 1001:9104 1001:9105 — —1002:9102 1002:9103 1002:9104 1002:9105 1003:9102 1003:9103 1003:91041003:9105 1004:9102 1004:9103 1004:9104 1004:9105 1005:9102 1005:91031005:9104 1005:9105 1006:9102 1006:9103 1006:9104 1006:9105 1007:91021007:9103 1007:9104 1007:9105 1008:9102 1008:9103 1008:9104 1008:91051009:9102 1009:9103 1009:9104 1009:9105 1010:9102 1010:9103 1010:91041010:9105 1011:9102 1011:9103 1011:9104 1011:9105 1012:9102 1012:91031012:9104 1012:9105 1013:9102 1013:9103 1013:9104 1013:9105 1014:91021014:9103 1014:9104 1014:9105 1015:9102 1015:9103 1015:9104 1015:91051016:9102 1016:9103 1016:9104 1016:9105 2001:9102 2001:9103 2001:91042001:9105 2002:9102 2002:9103 2002:9104 2002:9105 2003:9102 2003:91032003:9104 2003:9105 2004:9102 2004:9103 2004:9104 2004:9105 2005:91022005:9103 2005:9104 2005:9105 2006:9102 2006:9103 2006:9104 2006:91052007:9102 2007:9103 2007:9104 2007:9105 2008:9102 2008:9103 2008:91042008:9105 2009:9102 2009:9103 2009:9104 2009:9105 2010:9102 2010:91032010:9104 2010:9105 2011:9102 2011:9103 2011:9104 2011:9105 2012:91022012:9103 2012:9104 2012:9105

TABLE B Example combinations of a compound X with a compound Y. X:Y X:YX:Y X:Y X:Y X:Y 3001:9000 3001:9001 3001:9002 3001:9003 3001:90043001:9005 3002:9000 3002:9001 3002:9002 3002:9003 3002:9004 3002:90053003:9000 3003:9001 3003:9002 3003:9003 3003:9004 3003:9005 3004:90003004:9001 3004:9002 3004:9003 3004:9004 3004:9005 3005:9000 3005:90013005:9002 3005:9003 3005:9004 3005:9005 3006:9000 3006:9001 3006:90023006:9003 3006:9004 3006:9005 3007:9000 3007:9001 3007:9002 3007:90033007:9004 3007:9005 3008:9000 3008:9001 3008:9002 3008:9003 3008:90043008:9005 3009:9000 3009:9001 3009:9002 3009:9003 3009:9004 3009:90053010:9000 3010:9001 3010:9002 3010:9003 3010:9004 3010:9005 3011:90003011:9001 3011:9002 3011:9003 3011:9004 3011:9005 3012:9000 3012:90013012:9002 3012:9003 3012:9004 3012:9005 3013:9000 3013:9001 3013:90023013:9003 3013:9004 3013:9005 3014:9000 3014:9001 3014:9002 3014:90033014:9004 3014:9005 4001:9000 4001:9001 4001:9002 4001:9003 4001:90044001:9005 4002:9000 4002:9001 4002:9002 4002:9003 4002:9004 4002:90054003:9000 4003:9001 4003:9002 4003:9003 4003:9004 4003:9005 4004:90004004:9001 4004:9002 4004:9003 4004:9004 4004:9005 4005:9000 4005:90014005:9002 4005:9003 4005:9004 4005:9005 4006:9000 4006:9001 4006:90024006:9003 4006:9004 4006:9005 4007:9000 4007:9001 4007:9002 4007:90034007:9004 4007:9005 4008:9000 4008:9001 4008:9002 4008:9003 4008:90044008:9005 4009:9000 4009:9001 4009:9002 4009:9003 4009:9004 4009:90054010:9000 4010:9001 4010:9002 4010:9003 4010:9004 4010:9005 4011:90004011:9001 4011:9002 4011:9003 4011:9004 4011:9005 4012:9000 4012:90014012:9002 4012:9003 4012:9004 4012:9005 5001:9000 5001:9001 5001:90025001:9003 5001:9004 5001:9005 5002:9000 5002:9001 5002:9002 5002:90035002:9004 5002:9005 5003:9000 5003:9001 5003:9002 5003:9003 5003:90045003:9005 5004:9000 5004:9001 5004:9002 5004:9003 5004:9004 5004:90055005:9000 5005:9001 5005:9002 5005:9003 5005:9004 5005:9005 5006:90005006:9001 5006:9002 5006:9003 5006:9004 5006:9005 5007:9000 5007:90015007:9002 5007:9003 5007:9004 5007:9005 5008:9000 5008:9001 5008:90025008:9003 5008:9004 5008:9005 5009:9000 5009:9001 5009:9002 5009:90035009:9004 5009:9005 5010:9000 5010:9001 5010:9002 5010:9003 5010:90045010:9005 5011:9000 5011:9001 5011:9002 5011:9003 5011:9004 5011:90055012:9000 5012:9001 5012:9002 5012:9003 5012:9004 5012:9005 3001:90063001:9007 3001:9008 3001:9009 3001:9010 3001:9011 3002:9006 3002:90073002:9008 3002:9009 3002:9010 3002:9011 3003:9006 3003:9007 3003:90083003:9009 3003:9010 3003:9011 3004:9006 3004:9007 3004:9008 3004:90093004:9010 3004:9011 3005:9006 3005:9007 3005:9008 3005:9009 3005:90103005:9011 3006:9006 3006:9007 3006:9008 3006:9009 3006:9010 3006:90113007:9006 3007:9007 3007:9008 3007:9009 3007:9010 3007:9011 3008:90063008:9007 3008:9008 3008:9009 3008:9010 3008:9011 3009:9006 3009:90073009:9008 3009:9009 3009:9010 3009:9011 3010:9006 3010:9007 3010:90083010:9009 3010:9010 3010:9011 3011:9006 3011:9007 3011:9008 3011:90093011:9010 3011:9011 3012:9006 3012:9007 3012:9008 3012:9009 3012:90103012:9011 3013:9006 3013:9007 3013:9008 3013:9009 3013:9010 3013:90113014:9006 3014:9007 3014:9008 3014:9009 3014:9010 3014:9011 4001:90064001:9007 4001:9008 4001:9009 4001:9010 4001:9011 4002:9006 4002:90074002:9008 4002:9009 4002:9010 4002:9011 4003:9006 4003:9007 4003:90084003:9009 4003:9010 4003:9011 4004:9006 4004:9007 4004:9008 4004:90094004:9010 4004:9011 4005:9006 4005:9007 4005:9008 4005:9009 4005:90104005:9011 4006:9006 4006:9007 4006:9008 4006:9009 4006:9010 4006:90114007:9006 4007:9007 4007:9008 4007:9009 4007:9010 4007:9011 4008:90064008:9007 4008:9008 4008:9009 4008:9010 4008:9011 4009:9006 4009:90074009:9008 4009:9009 4009:9010 4009:9011 4010:9006 4010:9007 4010:90084010:9009 4010:9010 4010:9011 4011:9006 4011:9007 4011:9008 4011:90094011:9010 4011:9011 4012:9006 4012:9007 4012:9008 4012:9009 4012:90104012:9011 5001:9006 5001:9007 5001:9008 5001:9009 5001:9010 5001:90115002:9006 5002:9007 5002:9008 5002:9009 5002:9010 5002:9011 5003:90065003:9007 5003:9008 5003:9009 5003:9010 5003:9011 5004:9006 5004:90075004:9008 5004:9009 5004:9010 5004:9011 5005:9006 5005:9007 5005:90085005:9009 5005:9010 5005:9011 5006:9006 5006:9007 5006:9008 5006:90095006:9010 5006:9011 5007:9006 5007:9007 5007:9008 5007:9009 5007:90105007:9011 5008:9006 5008:9007 5008:9008 5008:9009 5008:9010 5008:90115009:9006 5009:9007 5009:9008 5009:9009 5009:9010 5009:9011 5010:90065010:9007 5010:9008 5010:9009 5010:9010 5010:9011 5011:9006 5011:90075011:9008 5011:9009 5011:9010 5011:9011 5012:9006 5012:9007 5012:90085012:9009 5012:9010 5012:9011 3001:9012 3001:9013 3001:9014 3001:90153001:9016 3001:9017 3002:9012 3002:9013 3002:9014 3002:9015 3002:90163002:9017 3003:9012 3003:9013 3003:9014 3003:9015 3003:9016 3003:90173004:9012 3004:9013 3004:9014 3004:9015 3004:9016 3004:9017 3005:90123005:9013 3005:9014 3005:9015 3005:9016 3005:9017 3006:9012 3006:90133006:9014 3006:9015 3006:9016 3006:9017 3007:9012 3007:9013 3007:90143007:9015 3007:9016 3007:9017 3008:9012 3008:9013 3008:9014 3008:90153008:9016 3008:9017 3009:9012 3009:9013 3009:9014 3009:9015 3009:90163009:9017 3010:9012 3010:9013 3010:9014 3010:9015 3010:9016 3010:90173011:9012 3011:9013 3011:9014 3011:9015 3011:9016 3011:9017 3012:90123012:9013 3012:9014 3012:9015 3012:9016 3012:9017 3013:9012 3013:90133013:9014 3013:9015 3013:9016 3013:9017 3014:9012 3014:9013 3014:90143014:9015 3014:9016 3014:9017 4001:9012 4001:9013 4001:9014 4001:90154001:9016 4001:9017 4002:9012 4002:9013 4002:9014 4002:9015 4002:90164002:9017 4003:9012 4003:9013 4003:9014 4003:9015 4003:9016 4003:90174004:9012 4004:9013 4004:9014 4004:9015 4004:9016 4004:9017 4005:90124005:9013 4005:9014 4005:9015 4005:9016 4005:9017 4006:9012 4006:90134006:9014 4006:9015 4006:9016 4006:9017 4007:9012 4007:9013 4007:90144007:9015 4007:9016 4007:9017 4008:9012 4008:9013 4008:9014 4008:90154008:9016 4008:9017 4009:9012 4009:9013 4009:9014 4009:9015 4009:90164009:9017 4010:9012 4010:9013 4010:9014 4010:9015 4010:9016 4010:90174011:9012 4011:9013 4011:9014 4011:9015 4011:9016 4011:9017 4012:90124012:9013 4012:9014 4012:9015 4012:9016 4012:9017 5001:9012 5001:90135001:9014 5001:9015 5001:9016 5001:9017 5002:9012 5002:9013 5002:90145002:9015 5002:9016 5002:9017 5003:9012 5003:9013 5003:9014 5003:90155003:9016 5003:9017 5004:9012 5004:9013 5004:9014 5004:9015 5004:90165004:9017 5005:9012 5005:9013 5005:9014 5005:9015 5005:9016 5005:90175006:9012 5006:9013 5006:9014 5006:9015 5006:9016 5006:9017 5007:90125007:9013 5007:9014 5007:9015 5007:9016 5007:9017 5008:9012 5008:90135008:9014 5008:9015 5008:9016 5008:9017 5009:9012 5009:9013 5009:90145009:9015 5009:9016 5009:9017 5010:9012 5010:9013 5010:9014 5010:90155010:9016 5010:9017 5011:9012 5011:9013 5011:9014 5011:9015 5011:90165011:9017 5012:9012 5012:9013 5012:9014 5012:9015 5012:9016 5012:90173001:9018 3001:9019 3001:9020 3001:9021 3001:9022 3001:9023 3002:90183002:9019 3002:9020 3002:9021 3002:9022 3002:9023 3003:9018 3003:90193003:9020 3003:9021 3003:9022 3003:9023 3004:9018 3004:9019 3004:90203004:9021 3004:9022 3004:9023 3005:9018 3005:9019 3005:9020 3005:90213005:9022 3005:9023 3006:9018 3006:9019 3006:9020 3006:9021 3006:90223006:9023 3007:9018 3007:9019 3007:9020 3007:9021 3007:9022 3007:90233008:9018 3008:9019 3008:9020 3008:9021 3008:9022 3008:9023 3009:90183009:9019 3009:9020 3009:9021 3009:9022 3009:9023 3010:9018 3010:90193010:9020 3010:9021 3010:9022 3010:9023 3011:9018 3011:9019 3011:90203011:9021 3011:9022 3011:9023 3012:9018 3012:9019 3012:9020 3012:90213012:9022 3012:9023 3013:9018 3013:9019 3013:9020 3013:9021 3013:90223013:9023 3014:9018 3014:9019 3014:9020 3014:9021 3014:9022 3014:90234001:9018 4001:9019 4001:9020 4001:9021 4001:9022 4001:9023 4002:90184002:9019 4002:9020 4002:9021 4002:9022 4002:9023 4003:9018 4003:90194003:9020 4003:9021 4003:9022 4003:9023 4004:9018 4004:9019 4004:90204004:9021 4004:9022 4004:9023 4005:9018 4005:9019 4005:9020 4005:90214005:9022 4005:9023 4006:9018 4006:9019 4006:9020 4006:9021 4006:90224006:9023 4007:9018 4007:9019 4007:9020 4007:9021 4007:9022 4007:90234008:9018 4008:9019 4008:9020 4008:9021 4008:9022 4008:9023 4009:90184009:9019 4009:9020 4009:9021 4009:9022 4009:9023 4010:9018 4010:90194010:9020 4010:9021 4010:9022 4010:9023 4011:9018 4011:9019 4011:90204011:9021 4011:9022 4011:9023 4012:9018 4012:9019 4012:9020 4012:90214012:9022 4012:9023 5001:9018 5001:9019 5001:9020 5001:9021 5001:90225001:9023 5002:9018 5002:9019 5002:9020 5002:9021 5002:9022 5002:90235003:9018 5003:9019 5003:9020 5003:9021 5003:9022 5003:9023 5004:90185004:9019 5004:9020 5004:9021 5004:9022 5004:9023 5005:9018 5005:90195005:9020 5005:9021 5005:9022 5005:9023 5006:9018 5006:9019 5006:90205006:9021 5006:9022 5006:9023 5007:9018 5007:9019 5007:9020 5007:90215007:9022 5007:9023 5008:9018 5008:9019 5008:9020 5008:9021 5008:90225008:9023 5009:9018 5009:9019 5009:9020 5009:9021 5009:9022 5009:90235010:9018 5010:9019 5010:9020 5010:9021 5010:9022 5010:9023 5011:90185011:9019 5011:9020 5011:9021 5011:9022 5011:9023 5012:9018 5012:90195012:9020 5012:9021 5012:9022 5012:9023 3001:9024 3001:9025 3001:90263001:9027 3001:9028 3001:9029 3002:9024 3002:9025 3002:9026 3002:90273002:9028 3002:9029 3003:9024 3003:9025 3003:9026 3003:9027 3003:90283003:9029 3004:9024 3004:9025 3004:9026 3004:9027 3004:9028 3004:90293005:9024 3005:9025 3005:9026 3005:9027 3005:9028 3005:9029 3006:90243006:9025 3006:9026 3006:9027 3006:9028 3006:9029 3007:9024 3007:90253007:9026 3007:9027 3007:9028 3007:9029 3008:9024 3008:9025 3008:90263008:9027 3008:9028 3008:9029 3009:9024 3009:9025 3009:9026 3009:90273009:9028 3009:9029 3010:9024 3010:9025 3010:9026 3010:9027 3010:90283010:9029 3011:9024 3011:9025 3011:9026 3011:9027 3011:9028 3011:90293012:9024 3012:9025 3012:9026 3012:9027 3012:9028 3012:9029 3013:90243013:9025 3013:9026 3013:9027 3013:9028 3013:9029 3014:9024 3014:90253014:9026 3014:9027 3014:9028 3014:9029 4001:9024 4001:9025 4001:90264001:9027 4001:9028 4001:9029 4002:9024 4002:9025 4002:9026 4002:90274002:9028 4002:9029 4003:9024 4003:9025 4003:9026 4003:9027 4003:90284003:9029 4004:9024 4004:9025 4004:9026 4004:9027 4004:9028 4004:90294005:9024 4005:9025 4005:9026 4005:9027 4005:9028 4005:9029 4006:90244006:9025 4006:9026 4006:9027 4006:9028 4006:9029 4007:9024 4007:90254007:9026 4007:9027 4007:9028 4007:9029 4008:9024 4008:9025 4008:90264008:9027 4008:9028 4008:9029 4009:9024 4009:9025 4009:9026 4009:90274009:9028 4009:9029 4010:9024 4010:9025 4010:9026 4010:9027 4010:90284010:9029 4011:9024 4011:9025 4011:9026 4011:9027 4011:9028 4011:90294012:9024 4012:9025 4012:9026 4012:9027 4012:9028 4012:9029 5001:90245001:9025 5001:9026 5001:9027 5001:9028 5001:9029 5002:9024 5002:90255002:9026 5002:9027 5002:9028 5002:9029 5003:9024 5003:9025 5003:90265003:9027 5003:9028 5003:9029 5004:9024 5004:9025 5004:9026 5004:90275004:9028 5004:9029 5005:9024 5005:9025 5005:9026 5005:9027 5005:90285005:9029 5006:9024 5006:9025 5006:9026 5006:9027 5006:9028 5006:90295007:9024 5007:9025 5007:9026 5007:9027 5007:9028 5007:9029 5008:90245008:9025 5008:9026 5008:9027 5008:9028 5008:9029 5009:9024 5009:90255009:9026 5009:9027 5009:9028 5009:9029 5010:9024 5010:9025 5010:90265010:9027 5010:9028 5010:9029 5011:9024 5011:9025 5011:9026 5011:90275011:9028 5011:9029 5012:9024 5012:9025 5012:9026 5012:9027 5012:90285012:9029 3001:9030 3001:9031 3001:9032 3001:9033 3001:9034 3001:90353002:9030 3002:9031 3002:9032 3002:9033 3002:9034 3002:9035 3003:90303003:9031 3003:9032 3003:9033 3003:9034 3003:9035 3004:9030 3004:90313004:9032 3004:9033 3004:9034 3004:9035 3005:9030 3005:9031 3005:90323005:9033 3005:9034 3005:9035 3006:9030 3006:9031 3006:9032 3006:90333006:9034 3006:9035 3007:9030 3007:9031 3007:9032 3007:9033 3007:90343007:9035 3008:9030 3008:9031 3008:9032 3008:9033 3008:9034 3008:90353009:9030 3009:9031 3009:9032 3009:9033 3009:9034 3009:9035 3010:90303010:9031 3010:9032 3010:9033 3010:9034 3010:9035 3011:9030 3011:90313011:9032 3011:9033 3011:9034 3011:9035 3012:9030 3012:9031 3012:90323012:9033 3012:9034 3012:9035 3013:9030 3013:9031 3013:9032 3013:90333013:9034 3013:9035 3014:9030 3014:9031 3014:9032 3014:9033 3014:90343014:9035 4001:9030 4001:9031 4001:9032 4001:9033 4001:9034 4001:90354002:9030 4002:9031 4002:9032 4002:9033 4002:9034 4002:9035 4003:90304003:9031 4003:9032 4003:9033 4003:9034 4003:9035 4004:9030 4004:90314004:9032 4004:9033 4004:9034 4004:9035 4005:9030 4005:9031 4005:90324005:9033 4005:9034 4005:9035 4006:9030 4006:9031 4006:9032 4006:90334006:9034 4006:9035 4007:9030 4007:9031 4007:9032 4007:9033 4007:90344007:9035 4008:9030 4008:9031 4008:9032 4008:9033 4008:9034 4008:90354009:9030 4009:9031 4009:9032 4009:9033 4009:9034 4009:9035 4010:90304010:9031 4010:9032 4010:9033 4010:9034 4010:9035 4011:9030 4011:90314011:9032 4011:9033 4011:9034 4011:9035 4012:9030 4012:9031 4012:90324012:9033 4012:9034 4012:9035 5001:9030 5001:9031 5001:9032 5001:90335001:9034 5001:9035 5002:9030 5002:9031 5002:9032 5002:9033 5002:90345002:9035 5003:9030 5003:9031 5003:9032 5003:9033 5003:9034 5003:90355004:9030 5004:9031 5004:9032 5004:9033 5004:9034 5004:9035 5005:90305005:9031 5005:9032 5005:9033 5005:9034 5005:9035 5006:9030 5006:90315006:9032 5006:9033 5006:9034 5006:9035 5007:9030 5007:9031 5007:90325007:9033 5007:9034 5007:9035 5008:9030 5008:9031 5008:9032 5008:90335008:9034 5008:9035 5009:9030 5009:9031 5009:9032 5009:9033 5009:90345009:9035 5010:9030 5010:9031 5010:9032 5010:9033 5010:9034 5010:90355011:9030 5011:9031 5011:9032 5011:9033 5011:9034 5011:9035 5012:90305012:9031 5012:9032 5012:9033 5012:9034 5012:9035 3001:9036 3001:90373001:9038 3001:9039 3001:9040 3001:9041 3002:9036 3002:9037 3002:90383002:9039 3002:9040 3002:9041 3003:9036 3003:9037 3003:9038 3003:90393003:9040 3003:9041 3004:9036 3004:9037 3004:9038 3004:9039 3004:90403004:9041 3005:9036 3005:9037 3005:9038 3005:9039 3005:9040 3005:90413006:9036 3006:9037 3006:9038 3006:9039 3006:9040 3006:9041 3007:90363007:9037 3007:9038 3007:9039 3007:9040 3007:9041 3008:9036 3008:90373008:9038 3008:9039 3008:9040 3008:9041 3009:9036 3009:9037 3009:90383009:9039 3009:9040 3009:9041 3010:9036 3010:9037 3010:9038 3010:90393010:9040 3010:9041 3011:9036 3011:9037 3011:9038 3011:9039 3011:90403011:9041 3012:9036 3012:9037 3012:9038 3012:9039 3012:9040 3012:90413013:9036 3013:9037 3013:9038 3013:9039 3013:9040 3013:9041 3014:90363014:9037 3014:9038 3014:9039 3014:9040 3014:9041 4001:9036 4001:90374001:9038 4001:9039 4001:9040 4001:9041 4002:9036 4002:9037 4002:90384002:9039 4002:9040 4002:9041 4003:9036 4003:9037 4003:9038 4003:90394003:9040 4003:9041 4004:9036 4004:9037 4004:9038 4004:9039 4004:90404004:9041 4005:9036 4005:9037 4005:9038 4005:9039 4005:9040 4005:90414006:9036 4006:9037 4006:9038 4006:9039 4006:9040 4006:9041 4007:90364007:9037 4007:9038 4007:9039 4007:9040 4007:9041 4008:9036 4008:90374008:9038 4008:9039 4008:9040 4008:9041 4009:9036 4009:9037 4009:90384009:9039 4009:9040 4009:9041 4010:9036 4010:9037 4010:9038 4010:90394010:9040 4010:9041 4011:9036 4011:9037 4011:9038 4011:9039 4011:90404011:9041 4012:9036 4012:9037 4012:9038 4012:9039 4012:9040 4012:90415001:9036 5001:9037 5001:9038 5001:9039 5001:9040 5001:9041 5002:90365002:9037 5002:9038 5002:9039 5002:9040 5002:9041 5003:9036 5003:90375003:9038 5003:9039 5003:9040 5003:9041 5004:9036 5004:9037 5004:90385004:9039 5004:9040 5004:9041 5005:9036 5005:9037 5005:9038 5005:90395005:9040 5005:9041 5006:9036 5006:9037 5006:9038 5006:9039 5006:90405006:9041 5007:9036 5007:9037 5007:9038 5007:9039 5007:9040 5007:90415008:9036 5008:9037 5008:9038 5008:9039 5008:9040 5008:9041 5009:90365009:9037 5009:9038 5009:9039 5009:9040 5009:9041 5010:9036 5010:90375010:9038 5010:9039 5010:9040 5010:9041 5011:9036 5011:9037 5011:90385011:9039 5011:9040 5011:9041 5012:9036 5012:9037 5012:9038 5012:90395012:9040 5012:9041 3001:9042 3001:9043 3001:9044 3001:9045 3001:90463001:9047 3002:9042 3002:9043 3002:9044 3002:9045 3002:9046 3002:90473003:9042 3003:9043 3003:9044 3003:9045 3003:9046 3003:9047 3004:90423004:9043 3004:9044 3004:9045 3004:9046 3004:9047 3005:9042 3005:90433005:9044 3005:9045 3005:9046 3005:9047 3006:9042 3006:9043 3006:90443006:9045 3006:9046 3006:9047 3007:9042 3007:9043 3007:9044 3007:90453007:9046 3007:9047 3008:9042 3008:9043 3008:9044 3008:9045 3008:90463008:9047 3009:9042 3009:9043 3009:9044 3009:9045 3009:9046 3009:90473010:9042 3010:9043 3010:9044 3010:9045 3010:9046 3010:9047 3011:90423011:9043 3011:9044 3011:9045 3011:9046 3011:9047 3012:9042 3012:90433012:9044 3012:9045 3012:9046 3012:9047 3013:9042 3013:9043 3013:90443013:9045 3013:9046 3013:9047 3014:9042 3014:9043 3014:9044 3014:90453014:9046 3014:9047 4001:9042 4001:9043 4001:9044 4001:9045 4001:90464001:9047 4002:9042 4002:9043 4002:9044 4002:9045 4002:9046 4002:90474003:9042 4003:9043 4003:9044 4003:9045 4003:9046 4003:9047 4004:90424004:9043 4004:9044 4004:9045 4004:9046 4004:9047 4005:9042 4005:90434005:9044 4005:9045 4005:9046 4005:9047 4006:9042 4006:9043 4006:90444006:9045 4006:9046 4006:9047 4007:9042 4007:9043 4007:9044 4007:90454007:9046 4007:9047 4008:9042 4008:9043 4008:9044 4008:9045 4008:90464008:9047 4009:9042 4009:9043 4009:9044 4009:9045 4009:9046 4009:90474010:9042 4010:9043 4010:9044 4010:9045 4010:9046 4010:9047 4011:90424011:9043 4011:9044 4011:9045 4011:9046 4011:9047 4012:9042 4012:90434012:9044 4012:9045 4012:9046 4012:9047 5001:9042 5001:9043 5001:90445001:9045 5001:9046 5001:9047 5002:9042 5002:9043 5002:9044 5002:90455002:9046 5002:9047 5003:9042 5003:9043 5003:9044 5003:9045 5003:90465003:9047 5004:9042 5004:9043 5004:9044 5004:9045 5004:9046 5004:90475005:9042 5005:9043 5005:9044 5005:9045 5005:9046 5005:9047 5006:90425006:9043 5006:9044 5006:9045 5006:9046 5006:9047 5007:9042 5007:90435007:9044 5007:9045 5007:9046 5007:9047 5008:9042 5008:9043 5008:90445008:9045 5008:9046 5008:9047 5009:9042 5009:9043 5009:9044 5009:90455009:9046 5009:9047 5010:9042 5010:9043 5010:9044 5010:9045 5010:90465010:9047 5011:9042 5011:9043 5011:9044 5011:9045 5011:9046 5011:90475012:9042 5012:9043 5012:9044 5012:9045 5012:9046 5012:9047 3001:90483001:9049 3001:9050 3001:9051 3001:9052 3001:9053 3002:9048 3002:90493002:9050 3002:9051 3002:9052 3002:9053 3003:9048 3003:9049 3003:90503003:9051 3003:9052 3003:9053 3004:9048 3004:9049 3004:9050 3004:90513004:9052 3004:9053 3005:9048 3005:9049 3005:9050 3005:9051 3005:90523005:9053 3006:9048 3006:9049 3006:9050 3006:9051 3006:9052 3006:90533007:9048 3007:9049 3007:9050 3007:9051 3007:9052 3007:9053 3008:90483008:9049 3008:9050 3008:9051 3008:9052 3008:9053 3009:9048 3009:90493009:9050 3009:9051 3009:9052 3009:9053 3010:9048 3010:9049 3010:90503010:9051 3010:9052 3010:9053 3011:9048 3011:9049 3011:9050 3011:90513011:9052 3011:9053 3012:9048 3012:9049 3012:9050 3012:9051 3012:90523012:9053 3013:9048 3013:9049 3013:9050 3013:9051 3013:9052 3013:90533014:9048 3014:9049 3014:9050 3014:9051 3014:9052 3014:9053 4001:90484001:9049 4001:9050 4001:9051 4001:9052 4001:9053 4002:9048 4002:90494002:9050 4002:9051 4002:9052 4002:9053 4003:9048 4003:9049 4003:90504003:9051 4003:9052 4003:9053 4004:9048 4004:9049 4004:9050 4004:90514004:9052 4004:9053 4005:9048 4005:9049 4005:9050 4005:9051 4005:90524005:9053 4006:9048 4006:9049 4006:9050 4006:9051 4006:9052 4006:90534007:9048 4007:9049 4007:9050 4007:9051 4007:9052 4007:9053 4008:90484008:9049 4008:9050 4008:9051 4008:9052 4008:9053 4009:9048 4009:90494009:9050 4009:9051 4009:9052 4009:9053 4010:9048 4010:9049 4010:90504010:9051 4010:9052 4010:9053 4011:9048 4011:9049 4011:9050 4011:90514011:9052 4011:9053 4012:9048 4012:9049 4012:9050 4012:9051 4012:90524012:9053 5001:9048 5001:9049 5001:9050 5001:9051 5001:9052 5001:90535002:9048 5002:9049 5002:9050 5002:9051 5002:9052 5002:9053 5003:90485003:9049 5003:9050 5003:9051 5003:9052 5003:9053 5004:9048 5004:90495004:9050 5004:9051 5004:9052 5004:9053 5005:9048 5005:9049 5005:90505005:9051 5005:9052 5005:9053 5006:9048 5006:9049 5006:9050 5006:90515006:9052 5006:9053 5007:9048 5007:9049 5007:9050 5007:9051 5007:90525007:9053 5008:9048 5008:9049 5008:9050 5008:9051 5008:9052 5008:90535009:9048 5009:9049 5009:9050 5009:9051 5009:9052 5009:9053 5010:90485010:9049 5010:9050 5010:9051 5010:9052 5010:9053 5011:9048 5011:90495011:9050 5011:9051 5011:9052 5011:9053 5012:9048 5012:9049 5012:90505012:9051 5012:9051 5012:9053 3001:9054 3001:9055 3001:9056 3001:90573001:9058 3001:9059 3002:9054 3002:9055 3002:9056 3002:9057 3002:90583002:9059 3003:9054 3003:9055 3003:9056 3003:9057 3003:9058 3003:90593004:9054 3004:9055 3004:9056 3004:9057 3004:9058 3004:9059 3005:90543005:9055 3005:9056 3005:9057 3005:9058 3005:9059 3006:9054 3006:90553006:9056 3006:9057 3006:9058 3006:9059 3007:9054 3007:9055 3007:90563007:9057 3007:9058 3007:9059 3008:9054 3008:9055 3008:9056 3008:90573008:9058 3008:9059 3009:9054 3009:9055 3009:9056 3009:9057 3009:90583009:9059 3010:9054 3010:9055 3010:9056 3010:9057 3010:9058 3010:90593011:9054 3011:9055 3011:9056 3011:9057 3011:9058 3011:9059 3012:90543012:9055 3012:9056 3012:9057 3012:9058 3012:9059 3013:9054 3013:90553013:9056 3013:9057 3013:9058 3013:9059 3014:9054 3014:9055 3014:90563014:9057 3014:9058 3014:9059 4001:9054 4001:9055 4001:9056 4001:90574001:9058 4001:9059 4002:9054 4002:9055 4002:9056 4002:9057 4002:90584002:9059 4003:9054 4003:9055 4003:9056 4003:9057 4003:9058 4003:90594004:9054 4004:9055 4004:9056 4004:9057 4004:9058 4004:9059 4005:90544005:9055 4005:9056 4005:9057 4005:9058 4005:9059 4006:9054 4006:90554006:9056 4006:9057 4006:9058 4006:9059 4007:9054 4007:9055 4007:90564007:9057 4007:9058 4007:9059 4008:9054 4008:9055 4008:9056 4008:90574008:9058 4008:9059 4009:9054 4009:9055 4009:9056 4009:9057 4009:90584009:9059 4010:9054 4010:9055 4010:9056 4010:9057 4010:9058 4010:90594011:9054 4011:9055 4011:9056 4011:9057 4011:9058 4011:9059 4012:90544012:9055 4012:9056 4012:9057 4012:9058 4012:9059 5001:9054 5001:90555001:9056 5001:9057 5001:9058 5001:9059 5002:9054 5002:9055 5002:90565002:9057 5002:9058 5002:9059 5003:9054 5003:9055 5003:9056 5003:90575003:9058 5003:9059 5004:9054 5004:9055 5004:9056 5004:9057 5004:90585004:9059 5005:9054 5005:9055 5005:9056 5005:9057 5005:9058 5005:90595006:9054 5006:9055 5006:9056 5006:9057 5006:9058 5006:9059 5007:90545007:9055 5007:9056 5007:9057 5007:9058 5007:9059 5008:9054 5008:90555008:9056 5008:9057 5008:9058 5008:9059 5009:9054 5009:9055 5009:90565009:9057 5009:9058 5009:9059 5010:9054 5010:9055 5010:9056 5010:90575010:9058 5010:9059 5011:9054 5011:9055 5011:9056 5011:9057 5011:90585011:9059 5012:9054 5012:9055 5012:9056 5012:9057 5012:9058 5012:90593001:9060 3001:9061 3001:9062 3001:9063 3001:9064 3001:9065 3002:90603002:9061 3002:9062 3002:9063 3002:9064 3002:9065 3003:9060 3003:90613003:9062 3003:9063 3003:9064 3003:9065 3004:9060 3004:9061 3004:90623004:9063 3004:9064 3004:9065 3005:9060 3005:9061 3005:9062 3005:90633005:9064 3005:9065 3006:9060 3006:9061 3006:9062 3006:9063 3006:90643006:9065 3007:9060 3007:9061 3007:9062 3007:9063 3007:9064 3007:90653008:9060 3008:9061 3008:9062 3008:9063 3008:9064 3008:9065 3009:90603009:9061 3009:9062 3009:9063 3009:9064 3009:9065 3010:9060 3010:90613010:9062 3010:9063 3010:9064 3010:9065 3011:9060 3011:9061 3011:90623011:9063 3011:9064 3011:9065 3012:9060 3012:9061 3012:9062 3012:90633012:9064 3012:9065 3013:9060 3013:9061 3013:9062 3013:9063 3013:90643013:9065 3014:9060 3014:9061 3014:9062 3014:9063 3014:9064 3014:90654001:9060 4001:9061 4001:9062 4001:9063 4001:9064 4001:9065 4002:90604002:9061 4002:9062 4002:9063 4002:9064 4002:9065 4003:9060 4003:90614003:9062 4003:9063 4003:9064 4003:9065 4004:9060 4004:9061 4004:90624004:9063 4004:9064 4004:9065 4005:9060 4005:9061 4005:9062 4005:90634005:9064 4005:9065 4006:9060 4006:9061 4006:9062 4006:9063 4006:90644006:9065 4007:9060 4007:9061 4007:9062 4007:9063 4007:9064 4007:90654008:9060 4008:9061 4008:9062 4008:9063 4008:9064 4008:9065 4009:90604009:9061 4009:9062 4009:9063 4009:9064 4009:9065 4010:9060 4010:90614010:9062 4010:9063 4010:9064 4010:9065 4011:9060 4011:9061 4011:90624011:9063 4011:9064 4011:9065 4012:9060 4012:9061 4012:9062 4012:90634012:9064 4012:9065 5001:9060 5001:9061 5001:9062 5001:9063 5001:90645001:9065 5002:9060 5002:9061 5002:9062 5002:9063 5002:9064 5002:90655003:9060 5003:9061 5003:9062 5003:9063 5003:9064 5003:9065 5004:90605004:9061 5004:9062 5004:9063 5004:9064 5004:9065 5005:9060 5005:90615005:9062 5005:9063 5005:9064 5005:9065 5006:9060 5006:9061 5006:90625006:9063 5006:9064 5006:9065 5007:9060 5007:9061 5007:9062 5007:90635007:9064 5007:9065 5008:9060 5008:9061 5008:9062 5008:9063 5008:90645008:9065 5009:9060 5009:9061 5009:9062 5009:9063 5009:9064 5009:90655010:9060 5010:9061 5010:9062 5010:9063 5010:9064 5010:9065 5011:90605011:9061 5011:9062 5011:9063 5011:9064 5011:9065 5012:9060 5012:90615012:9062 5012:9063 5012:9064 5012:9065 3001:9066 3001:9067 3001:90683001:9069 3001:9070 3001:9071 3002:9066 3002:9067 3002:9068 3002:90693002:9070 3002:9071 3003:9066 3003:9067 3003:9068 3003:9069 3003:90703003:9071 3004:9066 3004:9067 3004:9068 3004:9069 3004:9070 3004:90713005:9066 3005:9067 3005:9068 3005:9069 3005:9070 3005:9071 3006:90663006:9067 3006:9068 3006:9069 3006:9070 3006:9071 3007:9066 3007:90673007:9068 3007:9069 3007:9070 3007:9071 3008:9066 3008:9067 3008:90683008:9069 3008:9070 3008:9071 3009:9066 3009:9067 3009:9068 3009:90693009:9070 3009:9071 3010:9066 3010:9067 3010:9068 3010:9069 3010:90703010:9071 3011:9066 3011:9067 3011:9068 3011:9069 3011:9070 3011:90713012:9066 3012:9067 3012:9068 3012:9069 3012:9070 3012:9071 3013:90663013:9067 3013:9068 3013:9069 3013:9070 3013:9071 3014:9066 3014:90673014:9068 3014:9069 3014:9070 3014:9071 4001:9066 4001:9067 4001:90684001:9069 4001:9070 4001:9071 4002:9066 4002:9067 4002:9068 4002:90694002:9070 4002:9071 4003:9066 4003:9067 4003:9068 4003:9069 4003:90704003:9071 4004:9066 4004:9067 4004:9068 4004:9069 4004:9070 4004:90714005:9066 4005:9067 4005:9068 4005:9069 4005:9070 4005:9071 4006:90664006:9067 4006:9068 4006:9069 4006:9070 4006:9071 4007:9066 4007:90674007:9068 4007:9069 4007:9070 4007:9071 4008:9066 4008:9067 4008:90684008:9069 4008:9070 4008:9071 4009:9066 4009:9067 4009:9068 4009:90694009:9070 4009:9071 4010:9066 4010:9067 4010:9068 4010:9069 4010:90704010:9071 4011:9066 4011:9067 4011:9068 4011:9069 4011:9070 4011:90714012:9066 4012:9067 4012:9068 4012:9069 4012:9070 4012:9071 5001:90665001:9067 5001:9068 5001:9069 5001:9070 5001:9071 5002:9066 5002:90675002:9068 5002:9069 5002:9070 5002:9071 5003:9066 5003:9067 5003:90685003:9069 5003:9070 5003:9071 5004:9066 5004:9067 5004:9068 5004:90695004:9070 5004:9071 5005:9066 5005:9067 5005:9068 5005:9069 5005:90705005:9071 5006:9066 5006:9067 5006:9068 5006:9069 5006:9070 5006:90715007:9066 5007:9067 5007:9068 5007:9069 5007:9070 5007:9071 5008:90665008:9067 5008:9068 5008:9069 5008:9070 5008:9071 5009:9066 5009:90675009:9068 5009:9069 5009:9070 5009:9071 5010:9066 5010:9067 5010:90685010:9069 5010:9070 5010:9071 5011:9066 5011:9067 5011:9068 5011:90695011:9070 5011:9071 5012:9066 5012:9067 5012:9068 5012:9069 5012:90705012:9071 3001:9072 3001:9073 3001:9074 3001:9075 3001:9076 3001:90773002:9072 3002:9073 3002:9074 3002:9075 3002:9076 3002:9077 3003:90723003:9073 3003:9074 3003:9075 3003:9076 3003:9077 3004:9072 3004:90733004:9074 3004:9075 3004:9076 3004:9077 3005:9072 3005:9073 3005:90743005:9075 3005:9076 3005:9077 3006:9072 3006:9073 3006:9074 3006:90753006:9076 3006:9077 3007:9072 3007:9073 3007:9074 3007:9075 3007:90763007:9077 3008:9072 3008:9073 3008:9074 3008:9075 3008:9076 3008:90773009:9072 3009:9073 3009:9074 3009:9075 3009:9076 3009:9077 3010:90723010:9073 3010:9074 3010:9075 3010:9076 3010:9077 3011:9072 3011:90733011:9074 3011:9075 3011:9076 3011:9077 3012:9072 3012:9073 3012:90743012:9075 3012:9076 3012:9077 3013:9072 3013:9073 3013:9074 3013:90753013:9076 3013:9077 3014:9072 3014:9073 3014:9074 3014:9075 3014:90763014:9077 4001:9072 4001:9073 4001:9074 4001:9075 4001:9076 4001:90774002:9072 4002:9073 4002:9074 4002:9075 4002:9076 4002:9077 4003:90724003:9073 4003:9074 4003:9075 4003:9076 4003:9077 4004:9072 4004:90734004:9074 4004:9075 4004:9076 4004:9077 4005:9072 4005:9073 4005:90744005:9075 4005:9076 4005:9077 4006:9072 4006:9073 4006:9074 4006:90754006:9076 4006:9077 4007:9072 4007:9073 4007:9074 4007:9075 4007:90764007:9077 4008:9072 4008:9073 4008:9074 4008:9075 4008:9076 4008:90774009:9072 4009:9073 4009:9074 4009:9075 4009:9076 4009:9077 4010:90724010:9073 4010:9074 4010:9075 4010:9076 4010:9077 4011:9072 4011:90734011:9074 4011:9075 4011:9076 4011:9077 4012:9072 4012:9073 4012:90744012:9075 4012:9076 4012:9077 5001:9072 5001:9073 5001:9074 5001:90755001:9076 5001:9077 5002:9072 5002:9073 5002:9074 5002:9075 5002:90765002:9077 5003:9072 5003:9073 5003:9074 5003:9075 5003:9076 5003:90775004:9072 5004:9073 5004:9074 5004:9075 5004:9076 5004:9077 5005:90725005:9073 5005:9074 5005:9075 5005:9076 5005:9077 5006:9072 5006:90735006:9074 5006:9075 5006:9076 5006:9077 5007:9072 5007:9073 5007:90745007:9075 5007:9076 5007:9077 5008:9072 5008:9073 5008:9074 5008:90755008:9076 5008:9077 5009:9072 5009:9073 5009:9074 5009:9075 5009:90765009:9077 5010:9072 5010:9073 5010:9074 5010:9075 5010:9076 5010:90775011:9072 5011:9073 5011:9074 5011:9075 5011:9076 5011:9077 5012:90725012:9073 5012:9074 5012:9075 5012:9076 5012:9077 3001:9078 3001:90793001:9080 3001:9081 3001:9082 3001:9083 3002:9078 3002:9079 3002:90803002:9081 3002:9082 3002:9083 3003:9078 3003:9079 3003:9080 3003:90813003:9082 3003:9083 3004:9078 3004:9079 3004:9080 3004:9081 3004:90823004:9083 3005:9078 3005:9079 3005:9080 3005:9081 3005:9082 3005:90833006:9078 3006:9079 3006:9080 3006:9081 3006:9082 3006:9083 3007:90783007:9079 3007:9080 3007:9081 3007:9082 3007:9083 3008:9078 3008:90793008:9080 3008:9081 3008:9082 3008:9083 3009:9078 3009:9079 3009:90803009:9081 3009:9082 3009:9083 3010:9078 3010:9079 3010:9080 3010:90813010:9082 3010:9083 3011:9078 3011:9079 3011:9080 3011:9081 3011:90823011:9083 3012:9078 3012:9079 3012:9080 3012:9081 3012:9082 3012:90833013:9078 3013:9079 3013:9080 3013:9081 3013:9082 3013:9083 3014:90783014:9079 3014:9080 3014:9081 3014:9082 3014:9083 4001:9078 4001:90794001:9080 4001:9081 4001:9082 4001:9083 4002:9078 4002:9079 4002:90804002:9081 4002:9082 4002:9083 4003:9078 4003:9079 4003:9080 4003:90814003:9082 4003:9083 4004:9078 4004:9079 4004:9080 4004:9081 4004:90824004:9083 4005:9078 4005:9079 4005:9080 4005:9081 4005:9082 4005:90834006:9078 4006:9079 4006:9080 4006:9081 4006:9082 4006:9083 4007:90784007:9079 4007:9080 4007:9081 4007:9082 4007:9083 4008:9078 4008:90794008:9080 4008:9081 4008:9082 4008:9083 4009:9078 4009:9079 4009:90804009:9081 4009:9082 4009:9083 4010:9078 4010:9079 4010:9080 4010:90814010:9082 4010:9083 4011:9078 4011:9079 4011:9080 4011:9081 4011:90824011:9083 4012:9078 4012:9079 4012:9080 4012:9081 4012:9082 4012:90835001:9078 5001:9079 5001:9080 5001:9081 5001:9082 5001:9083 5002:90785002:9079 5002:9080 5002:9081 5002:9082 5002:9083 5003:9078 5003:90795003:9080 5003:9081 5003:9082 5003:9083 5004:9078 5004:9079 5004:90805004:9081 5004:9082 5004:9083 5005:9078 5005:9079 5005:9080 5005:90815005:9082 5005:9083 5006:9078 5006:9079 5006:9080 5006:9081 5006:90825006:9083 5007:9078 5007:9079 5007:9080 5007:9081 5007:9082 5007:90835008:9078 5008:9079 5008:9080 5008:9081 5008:9082 5008:9083 5009:90785009:9079 5009:9080 5009:9081 5009:9082 5009:9083 5010:9078 5010:90795010:9080 5010:9081 5010:9082 5010:9083 5011:9078 5011:9079 5011:90805011:9081 5011:9082 5011:9083 5012:9078 5012:9079 5012:9080 5012:90815012:9082 5012:9083 3001:9084 3001:9085 3001:9086 3001:9087 3001:90883001:9089 3002:9084 3002:9085 3002:9086 3002:9087 3002:9088 3002:90893003:9084 3003:9085 3003:9086 3003:9087 3003:9088 3003:9089 3004:90843004:9085 3004:9086 3004:9087 3004:9088 3004:9089 3005:9084 3005:90853005:9086 3005:9087 3005:9088 3005:9089 3006:9084 3006:9085 3006:90863006:9087 3006:9088 3006:9089 3007:9084 3007:9085 3007:9086 3007:90873007:9088 3007:9089 3008:9084 3008:9085 3008:9086 3008:9087 3008:90883008:9089 3009:9084 3009:9085 3009:9086 3009:9087 3009:9088 3009:90893010:9084 3010:9085 3010:9086 3010:9087 3010:9088 3010:9089 3011:90843011:9085 3011:9086 3011:9087 3011:9088 3011:9089 3012:9084 3012:90853012:9086 3012:9087 3012:9088 3012:9089 3013:9084 3013:9085 3013:90863013:9087 3013:9088 3013:9089 3014:9084 3014:9085 3014:9086 3014:90873014:9088 3014:9089 4001:9084 4001:9085 4001:9086 4001:9087 4001:90884001:9089 4002:9084 4002:9085 4002:9086 4002:9087 4002:9088 4002:90894003:9084 4003:9085 4003:9086 4003:9087 4003:9088 4003:9089 4004:90844004:9085 4004:9086 4004:9087 4004:9088 4004:9089 4005:9084 4005:90854005:9086 4005:9087 4005:9088 4005:9089 4006:9084 4006:9085 4006:90864006:9087 4006:9088 4006:9089 4007:9084 4007:9085 4007:9086 4007:90874007:9088 4007:9089 4008:9084 4008:9085 4008:9086 4008:9087 4008:90884008:9089 4009:9084 4009:9085 4009:9086 4009:9087 4009:9088 4009:90894010:9084 4010:9085 4010:9086 4010:9087 4010:9088 4010:9089 4011:90844011:9085 4011:9086 4011:9087 4011:9088 4011:9089 4012:9084 4012:90854012:9086 4012:9087 4012:9088 4012:9089 5001:9084 5001:9085 5001:90865001:9087 5001:9088 5001:9089 5002:9084 5002:9085 5002:9086 5002:90875002:9088 5002:9089 5003:9084 5003:9085 5003:9086 5003:9087 5003:90885003:9089 5004:9084 5004:9085 5004:9086 5004:9087 5004:9088 5004:90895005:9084 5005:9085 5005:9086 5005:9087 5005:9088 5005:9089 5006:90845006:9085 5006:9086 5006:9087 5006:9088 5006:9089 5007:9084 5007:90855007:9086 5007:9087 5007:9088 5007:9089 5008:9084 5008:9085 5008:90865008:9087 5008:9088 5008:9089 5009:9084 5009:9085 5009:9086 5009:90875009:9088 5009:9089 5010:9084 5010:9085 5010:9086 5010:9087 5010:90885010:9089 5011:9084 5011:9085 5011:9086 5011:9087 5011:9088 5011:90895012:9084 5012:9085 5012:9086 5012:9087 5012:9088 5012:9089 3001:90903001:9091 3001:9092 3001:9093 3001:9094 3001:9095 3002:9090 3002:90913002:9092 3002:9093 3002:9094 3002:9095 3003:9090 3003:9091 3003:90923003:9093 3003:9094 3003:9095 3004:9090 3004:9091 3004:9092 3004:90933004:9094 3004:9095 3005:9090 3005:9091 3005:9092 3005:9093 3005:90943005:9095 3006:9090 3006:9091 3006:9092 3006:9093 3006:9094 3006:90953007:9090 3007:9091 3007:9092 3007:9093 3007:9094 3007:9095 3008:90903008:9091 3008:9092 3008:9093 3008:9094 3008:9095 3009:9090 3009:90913009:9092 3009:9093 3009:9094 3009:9095 3010:9090 3010:9091 3010:90923010:9093 3010:9094 3010:9095 3011:9090 3011:9091 3011:9092 3011:90933011:9094 3011:9095 3012:9090 3012:9091 3012:9092 3012:9093 3012:90943012:9095 3013:9090 3013:9091 3013:9092 3013:9093 3013:9094 3013:90953014:9090 3014:9091 3014:9092 3014:9093 3014:9094 3014:9095 4001:90904001:9091 4001:9092 4001:9093 4001:9094 4001:9095 4002:9090 4002:90914002:9092 4002:9093 4002:9094 4002:9095 4003:9090 4003:9091 4003:90924003:9093 4003:9094 4003:9095 4004:9090 4004:9091 4004:9092 4004:90934004:9094 4004:9095 4005:9090 4005:9091 4005:9092 4005:9093 4005:90944005:9095 4006:9090 4006:9091 4006:9092 4006:9093 4006:9094 4006:90954007:9090 4007:9091 4007:9092 4007:9093 4007:9094 4007:9095 4008:90904008:9091 4008:9092 4008:9093 4008:9094 4008:9095 4009:9090 4009:90914009:9092 4009:9093 4009:9094 4009:9095 4010:9090 4010:9091 4010:90924010:9093 4010:9094 4010:9095 4011:9090 4011:9091 4011:9092 4011:90934011:9094 4011:9095 4012:9090 4012:9091 4012:9092 4012:9093 4012:90944012:9095 5001:9090 5001:9091 5001:9092 5001:9093 5001:9094 5001:90955002:9090 5002:9091 5002:9092 5002:9093 5002:9094 5002:9095 5003:90905003:9091 5003:9092 5003:9093 5003:9094 5003:9095 5004:9090 5004:90915004:9092 5004:9093 5004:9094 5004:9095 5005:9090 5005:9091 5005:90925005:9093 5005:9094 5005:9095 5006:9090 5006:9091 5006:9092 5006:90935006:9094 5006:9095 5007:9090 5007:9091 5007:9092 5007:9093 5007:90945007:9095 5008:9090 5008:9091 5008:9092 5008:9093 5008:9094 5008:90955009:9090 5009:9091 5009:9092 5009:9093 5009:9094 5009:9095 5010:90905010:9091 5010:9092 5010:9093 5010:9094 5010:9095 5011:9090 5011:90915011:9092 5011:9093 5011:9094 5011:9095 5012:9090 5012:9091 5012:90925012:9093 5012:9094 5012:9095 3001:9096 3001:9097 3001:9098 3001:90993001:9100 3001:9101 3002:9096 3002:9097 3002:9098 3002:9099 3002:91003002:9101 3003:9096 3003:9097 3003:9098 3003:9099 3003:9100 3003:91013004:9096 3004:9097 3004:9098 3004:9099 3004:9100 3004:9101 3005:90963005:9097 3005:9098 3005:9099 3005:9100 3005:9101 3006:9096 3006:90973006:9098 3006:9099 3006:9100 3006:9101 3007:9096 3007:9097 3007:90983007:9099 3007:9100 3007:9101 3008:9096 3008:9097 3008:9098 3008:90993008:9100 3008:9101 3009:9096 3009:9097 3009:9098 3009:9099 3009:91003009:9101 3010:9096 3010:9097 3010:9098 3010:9099 3010:9100 3010:91013011:9096 3011:9097 3011:9098 3011:9099 3011:9100 3011:9101 3012:90963012:9097 3012:9098 3012:9099 3012:9100 3012:9101 3013:9096 3013:90973013:9098 3013:9099 3013:9100 3013:9101 3014:9096 3014:9097 3014:90983014:9099 3014:9100 3014:9101 4001:9096 4001:9097 4001:9098 4001:90994001:9100 4001:9101 4002:9096 4002:9097 4002:9098 4002:9099 4002:91004002:9101 4003:9096 4003:9097 4003:9098 4003:9099 4003:9100 4003:91014004:9096 4004:9097 4004:9098 4004:9099 4004:9100 4004:9101 4005:90964005:9097 4005:9098 4005:9099 4005:9100 4005:9101 4006:9096 4006:90974006:9098 4006:9099 4006:9100 4006:9101 4007:9096 4007:9097 4007:90984007:9099 4007:9100 4007:9101 4008:9096 4008:9097 4008:9098 4008:90994008:9100 4008:9101 4009:9096 4009:9097 4009:9098 4009:9099 4009:91004009:9101 4010:9096 4010:9097 4010:9098 4010:9099 4010:9100 4010:91014011:9096 4011:9097 4011:9098 4011:9099 4011:9100 4011:9101 4012:90964012:9097 4012:9098 4012:9099 4012:9100 4012:9101 5001:9096 5001:90975001:9098 5001:9099 5001:9100 5001:9101 5002:9096 5002:9097 5002:90985002:9099 5002:9100 5002:9101 5003:9096 5003:9097 5003:9098 5003:90995003:9100 5003:9101 5004:9096 5004:9097 5004:9098 5004:9099 5004:91005004:9101 5005:9096 5005:9097 5005:9098 5005:9099 5005:9100 5005:91015006:9096 5006:9097 5006:9098 5006:9099 5006:9100 5006:9101 5007:90965007:9097 5007:9098 5007:9099 5007:9100 5007:9101 5008:9096 5008:90975008:9098 5008:9099 5008:9100 5008:9101 5009:9096 5009:9097 5009:90985009:9099 5009:9100 5009:9101 5010:9096 5010:9097 5010:9098 5010:90995010:9100 5010:9101 5011:9096 5011:9097 5011:9098 5011:9099 5011:91005011:9101 5012:9096 5012:9097 5012:9098 5012:9099 5012:9100 5012:91013001:9102 3001:9103 3001:9104 3001:9105 — — 3002:9102 3002:91033002:9104 3002:9105 3003:9102 3003:9103 3003:9104 3003:9105 3004:91023004:9103 3004:9104 3004:9105 3005:9102 3005:9103 3005:9104 3005:91053006:9102 3006:9103 3006:9104 3006:9105 3007:9102 3007:9103 3007:91043007:9105 3008:9102 3008:9103 3008:9104 3008:9105 3009:9102 3009:91033009:9104 3009:9105 3010:9102 3010:9103 3010:9104 3010:9105 3011:91023011:9103 3011:9104 3011:9105 3012:9102 3012:9103 3012:9104 3012:91053013:9102 3013:9103 3013:9104 3013:9105 3014:9102 3014:9103 3014:91043014:9105 4001:9102 4001:9103 4001:9104 4001:9105 4002:9102 4002:91034002:9104 4002:9105 4003:9102 4003:9103 4003:9104 4003:9105 4004:91024004:9103 4004:9104 4004:9105 4005:9102 4005:9103 4005:9104 4005:91054006:9102 4006:9103 4006:9104 4006:9105 4007:9102 4007:9103 4007:91044007:9105 4008:9102 4008:9103 4008:9104 4008:9105 4009:9102 4009:91034009:9104 4009:9105 4010:9102 4010:9103 4010:9104 4010:9105 4011:91024011:9103 4011:9104 4011:9105 4012:9102 4012:9103 4012:9104 4012:91055001:9102 5001:9103 5001:9104 5001:9105 5002:9102 5002:9103 5002:91045002:9105 5003:9102 5003:9103 5003:9104 5003:9105 5004:9102 5004:91035004:9104 5004:9105 5005:9102 5005:9103 5005:9104 5005:9105 5006:91025006:9103 5006:9104 5006:9105 5007:9102 5007:9103 5007:9104 5007:91055008:9102 5008:9103 5008:9104 5008:9105 5009:9102 5009:9103 5009:91045009:9105 5010:9102 5010:9103 5010:9104 5010:9105 5011:9102 5011:91035011:9104 5011:9105 5012:9102 5012:9103 5012:9104 5012:9105

TABLE C Example combinations of a compound X with a compound Y. X:Y X:YX:Y X:Y X:Y X:Y 9000:7000 9001:7000 9002:7000 9003:7000 9004:70009005:7000 9000:7001 9001:7001 9002:7001 9003:7001 9004:7001 9005:70019000:7002 9001:7002 9002:7002 9003:7002 9004:7002 9005:7002 9000:70039001:7003 9002:7003 9003:7003 9004:7003 9005:7003 9000:7004 9001:70049002:7004 9003:7004 9004:7004 9005:7004 9000:7005 9001:7005 9002:70059003:7005 9004:7005 9005:7005 9000:7006 9001:7006 9002:7006 9003:70069004:7006 9005:7006 9000:7007 9001:7007 9002:7007 9003:7007 9004:70079005:7007 9000:7008 9001:7008 9002:7008 9003:7008 9004:7008 9005:70089000:7009 9001:7009 9002:7009 9003:7009 9004:7009 9005:7009 9000:70109001:7010 9002:7010 9003:7010 9004:7010 9005:7010 9000:7011 9001:70119002:7011 9003:7011 9004:7011 9005:7011 9000:7012 9001:7012 9002:70129003:7012 9004:7012 9005:7012 9000:7013 9001:7013 9002:7013 9003:70139004:7013 9005:7013 9000:7014 9001:7014 9002:7014 9003:7014 9004:70149005:7014 9000:7015 9001:7015 9002:7015 9003:7015 9004:7015 9005:70159000:7016 9001:7016 9002:7016 9003:7016 9004:7016 9005:7016 9000:70179001:7017 9002:7017 9003:7017 9004:7017 9005:7017 9000:7018 9001:70189002:7018 9003:7018 9004:7018 9005:7018 9000:7019 9001:7019 9002:70199003:7019 9004:7019 9005:7019 9000:7020 9001:7020 9002:7020 9003:70209004:7020 9005:7020 9000:7021 9001:7021 9002:7021 9003:7021 9004:70219005:7021 9000:7022 9001:7022 9002:7022 9003:7022 9004:7022 9005:70229000:7023 9001:7023 9002:7023 9003:7023 9004:7023 9005:7023 9000:70249001:7024 9002:7024 9003:7024 9004:7024 9005:7024 9000:7025 9001:70259002:7025 9003:7025 9004:7025 9005:7025 9000:7026 9001:7026 9002:70269003:7026 9004:7026 9005:7026 9000:7027 9001:7027 9002:7027 9003:70279004:7027 9005:7027 9006:7000 9007:7000 9008:7000 9009:7000 9010:70009011:7000 9006:7001 9007:7001 9008:7001 9009:7001 9010:7001 9011:70019006:7002 9007:7002 9008:7002 9009:7002 9010:7002 9011:7002 9006:70039007:7003 9008:7003 9009:7003 9010:7003 9011:7003 9006:7004 9007:70049008:7004 9009:7004 9010:7004 9011:7004 9006:7005 9007:7005 9008:70059009:7005 9010:7005 9011:7005 9006:7006 9007:7006 9008:7006 9009:70069010:7006 9011:7006 9006:7007 9007:7007 9008:7007 9009:7007 9010:70079011:7007 9006:7008 9007:7008 9008:7008 9009:7008 9010:7008 9011:70089006:7009 9007:7009 9008:7009 9009:7009 9010:7009 9011:7009 9006:70109007:7010 9008:7010 9009:7010 9010:7010 9011:7010 9006:7011 9007:70119008:7011 9009:7011 9010:7011 9011:7011 9006:7012 9007:7012 9008:70129009:7012 9010:7012 9011:7012 9006:7013 9007:7013 9008:7013 9009:70139010:7013 9011:7013 9006:7014 9007:7014 9008:7014 9009:7014 9010:70149011:7014 9006:7015 9007:7015 9008:7015 9009:7015 9010:7015 9011:70159006:7016 9007:7016 9008:7016 9009:7016 9010:7016 9011:7016 9006:70179007:7017 9008:7017 9009:7017 9010:7017 9011:7017 9006:7018 9007:70189008:7018 9009:7018 9010:7018 9011:7018 9006:7019 9007:7019 9008:70199009:7019 9010:7019 9011:7019 9006:7020 9007:7020 9008:7020 9009:70209010:7020 9011:7020 9006:7021 9007:7021 9008:7021 9009:7021 9010:70219011:7021 9006:7022 9007:7022 9008:7022 9009:7022 9010:7022 9011:70229006:7023 9007:7023 9008:7023 9009:7023 9010:7023 9011:7023 9006:70249007:7024 9008:7024 9009:7024 9010:7024 9011:7024 9006:7025 9007:70259008:7025 9009:7025 9010:7025 9011:7025 9006:7026 9007:7026 9008:70269009:7026 9010:7026 9011:7026 9006:7027 9007:7027 9008:7027 9009:70279010:7027 9011:7027 9012:7000 9013:7000 9014:7000 9015:7000 9016:70009017:7000 9012:7001 9013:7001 9014:7001 9015:7001 9016:7001 9017:70019012:7002 9013:7002 9014:7002 9015:7002 9016:7002 9017:7002 9012:70039013:7003 9014:7003 9015:7003 9016:7003 9017:7003 9012:7004 9013:70049014:7004 9015:7004 9016:7004 9017:7004 9012:7005 9013:7005 9014:70059015:7005 9016:7005 9017:7005 9012:7006 9013:7006 9014:7006 9015:70069016:7006 9017:7006 9012:7007 9013:7007 9014:7007 9015:7007 9016:70079017:7007 9012:7008 9013:7008 9014:7008 9015:7008 9016:7008 9017:70089012:7009 9013:7009 9014:7009 9015:7009 9016:7009 9017:7009 9012:70109013:7010 9014:7010 9015:7010 9016:7010 9017:7010 9012:7011 9013:70119014:7011 9015:7011 9016:7011 9017:7011 9012:7012 9013:7012 9014:70129015:7012 9016:7012 9017:7012 9012:7013 9013:7013 9014:7013 9015:70139016:7013 9017:7013 9012:7014 9013:7014 9014:7014 9015:7014 9016:70149017:7014 9012:7015 9013:7015 9014:7015 9015:7015 9016:7015 9017:70159012:7016 9013:7016 9014:7016 9015:7016 9016:7016 9017:7016 9012:70179013:7017 9014:7017 9015:7017 9016:7017 9017:7017 9012:7018 9013:70189014:7018 9015:7018 9016:7018 9017:7018 9012:7019 9013:7019 9014:70199015:7019 9016:7019 9017:7019 9012:7020 9013:7020 9014:7020 9015:70209016:7020 9017:7020 9012:7021 9013:7021 9014:7021 9015:7021 9016:70219017:7021 9012:7022 9013:7022 9014:7022 9015:7022 9016:7022 9017:70229012:7023 9013:7023 9014:7023 9015:7023 9016:7023 9017:7023 9012:70249013:7024 9014:7024 9015:7024 9016:7024 9017:7024 9012:7025 9013:70259014:7025 9015:7025 9016:7025 9017:7025 9012:7026 9013:7026 9014:70269015:7026 9016:7026 9017:7026 9012:7027 9013:7027 9014:7027 9015:70279016:7027 9017:7027 9018:7000 9019:7000 9020:7000 9021:7000 9022:70009023:7000 9018:7001 9019:7001 9020:7001 9021:7001 9022:7001 9023:70019018:7002 9019:7002 9020:7002 9021:7002 9022:7002 9023:7002 9018:70039019:7003 9020:7003 9021:7003 9022:7003 9023:7003 9018:7004 9019:70049020:7004 9021:7004 9022:7004 9023:7004 9018:7005 9019:7005 9020:70059021:7005 9022:7005 9023:7005 9018:7006 9019:7006 9020:7006 9021:70069022:7006 9023:7006 9018:7007 9019:7007 9020:7007 9021:7007 9022:70079023:7007 9018:7008 9019:7008 9020:7008 9021:7008 9022:7008 9023:70089018:7009 9019:7009 9020:7009 9021:7009 9022:7009 9023:7009 9018:70109019:7010 9020:7010 9021:7010 9022:7010 9023:7010 9018:7011 9019:70119020:7011 9021:7011 9022:7011 9023:7011 9018:7012 9019:7012 9020:70129021:7012 9022:7012 9023:7012 9018:7013 9019:7013 9020:7013 9021:70139022:7013 9023:7013 9018:7014 9019:7014 9020:7014 9021:7014 9022:70149023:7014 9018:7015 9019:7015 9020:7015 9021:7015 9022:7015 9023:70159018:7016 9019:7016 9020:7016 9021:7016 9022:7016 9023:7016 9018:70179019:7017 9020:7017 9021:7017 9022:7017 9023:7017 9018:7018 9019:70189020:7018 9021:7018 9022:7018 9023:7018 9018:7019 9019:7019 9020:70199021:7019 9022:7019 9023:7019 9018:7020 9019:7020 9020:7020 9021:70209022:7020 9023:7020 9018:7021 9019:7021 9020:7021 9021:7021 9022:70219023:7021 9018:7022 9019:7022 9020:7022 9021:7022 9022:7022 9023:70229018:7023 9019:7023 9020:7023 9021:7023 9022:7023 9023:7023 9018:70249019:7024 9020:7024 9021:7024 9022:7024 9023:7024 9018:7025 9019:70259020:7025 9021:7025 9022:7025 9023:7025 9018:7026 9019:7026 9020:70269021:7026 9022:7026 9023:7026 9018:7027 9019:7027 9020:7027 9021:70279022:7027 9023:7027 9024:7000 9025:7000 9026:7000 9027:7000 9028:70009029:7000 9024:7001 9025:7001 9026:7001 9027:7001 9028:7001 9029:70019024:7002 9025:7002 9026:7002 9027:7002 9028:7002 9029:7002 9024:70039025:7003 9026:7003 9027:7003 9028:7003 9029:7003 9024:7004 9025:70049026:7004 9027:7004 9028:7004 9029:7004 9024:7005 9025:7005 9026:70059027:7005 9028:7005 9029:7005 9024:7006 9025:7006 9026:7006 9027:70069028:7006 9029:7006 9024:7007 9025:7007 9026:7007 9027:7007 9028:70079029:7007 9024:7008 9025:7008 9026:7008 9027:7008 9028:7008 9029:70089024:7009 9025:7009 9026:7009 9027:7009 9028:7009 9029:7009 9024:70109025:7010 9026:7010 9027:7010 9028:7010 9029:7010 9024:7011 9025:70119026:7011 9027:7011 9028:7011 9029:7011 9024:7012 9025:7012 9026:70129027:7012 9028:7012 9029:7012 9024:7013 9025:7013 9026:7013 9027:70139028:7013 9029:7013 9024:7014 9025:7014 9026:7014 9027:7014 9028:70149029:7014 9024:7015 9025:7015 9026:7015 9027:7015 9028:7015 9029:70159024:7016 9025:7016 9026:7016 9027:7016 9028:7016 9029:7016 9024:70179025:7017 9026:7017 9027:7017 9028:7017 9029:7017 9024:7018 9025:70189026:7018 9027:7018 9028:7018 9029:7018 9024:7019 9025:7019 9026:70199027:7019 9028:7019 9029:7019 9024:7020 9025:7020 9026:7020 9027:70209028:7020 9029:7020 9024:7021 9025:7021 9026:7021 9027:7021 9028:70219029:7021 9024:7022 9025:7022 9026:7022 9027:7022 9028:7022 9029:70229024:7023 9025:7023 9026:7023 9027:7023 9028:7023 9029:7023 9024:70249025:7024 9026:7024 9027:7024 9028:7024 9029:7024 9024:7025 9025:70259026:7025 9027:7025 9028:7025 9029:7025 9024:7026 9025:7026 9026:70269027:7026 9028:7026 9029:7026 9024:7027 9025:7027 9026:7027 9027:70279028:7027 9029:7027 9030:7000 9031:7000 9032:7000 9033:7000 9034:70009035:7000 9030:7001 9031:7001 9032:7001 9033:7001 9034:7001 9035:70019030:7002 9031:7002 9032:7002 9033:7002 9034:7002 9035:7002 9030:70039031:7003 9032:7003 9033:7003 9034:7003 9035:7003 9030:7004 9031:70049032:7004 9033:7004 9034:7004 9035:7004 9030:7005 9031:7005 9032:70059033:7005 9034:7005 9035:7005 9030:7006 9031:7006 9032:7006 9033:70069034:7006 9035:7006 9030:7007 9031:7007 9032:7007 9033:7007 9034:70079035:7007 9030:7008 9031:7008 9032:7008 9033:7008 9034:7008 9035:70089030:7009 9031:7009 9032:7009 9033:7009 9034:7009 9035:7009 9030:70109031:7010 9032:7010 9033:7010 9034:7010 9035:7010 9030:7011 9031:70119032:7011 9033:7011 9034:7011 9035:7011 9030:7012 9031:7012 9032:70129033:7012 9034:7012 9035:7012 9030:7013 9031:7013 9032:7013 9033:70139034:7013 9035:7013 9030:7014 9031:7014 9032:7014 9033:7014 9034:70149035:7014 9030:7015 9031:7015 9032:7015 9033:7015 9034:7015 9035:70159030:7016 9031:7016 9032:7016 9033:7016 9034:7016 9035:7016 9030:70179031:7017 9032:7017 9033:7017 9034:7017 9035:7017 9030:7018 9031:70189032:7018 9033:7018 9034:7018 9035:7018 9030:7019 9031:7019 9032:70199033:7019 9034:7019 9035:7019 9030:7020 9031:7020 9032:7020 9033:70209034:7020 9035:7020 9030:7021 9031:7021 9032:7021 9033:7021 9034:70219035:7021 9030:7022 9031:7022 9032:7022 9033:7022 9034:7022 9035:70229030:7023 9031:7023 9032:7023 9033:7023 9034:7023 9035:7023 9030:70249031:7024 9032:7024 9033:7024 9034:7024 9035:7024 9030:7025 9031:70259032:7025 9033:7025 9034:7025 9035:7025 9030:7026 9031:7026 9032:70269033:7026 9034:7026 9035:7026 9030:7027 9031:7027 9032:7027 9033:70279034:7027 9035:7027 9036:7000 9037:7000 9038:7000 9039:7000 9040:70009041:7000 9036:7001 9037:7001 9038:7001 9039:7001 9040:7001 9041:70019036:7002 9037:7002 9038:7002 9039:7002 9040:7002 9041:7002 9036:70039037:7003 9038:7003 9039:7003 9040:7003 9041:7003 9036:7004 9037:70049038:7004 9039:7004 9040:7004 9041:7004 9036:7005 9037:7005 9038:70059039:7005 9040:7005 9041:7005 9036:7006 9037:7006 9038:7006 9039:70069040:7006 9041:7006 9036:7007 9037:7007 9038:7007 9039:7007 9040:70079041:7007 9036:7008 9037:7008 9038:7008 9039:7008 9040:7008 9041:70089036:7009 9037:7009 9038:7009 9039:7009 9040:7009 9041:7009 9036:70109037:7010 9038:7010 9039:7010 9040:7010 9041:7010 9036:7011 9037:70119038:7011 9039:7011 9040:7011 9041:7011 9036:7012 9037:7012 9038:70129039:7012 9040:7012 9041:7012 9036:7013 9037:7013 9038:7013 9039:70139040:7013 9041:7013 9036:7014 9037:7014 9038:7014 9039:7014 9040:70149041:7014 9036:7015 9037:7015 9038:7015 9039:7015 9040:7015 9041:70159036:7016 9037:7016 9038:7016 9039:7016 9040:7016 9041:7016 9036:70179037:7017 9038:7017 9039:7017 9040:7017 9041:7017 9036:7018 9037:70189038:7018 9039:7018 9040:7018 9041:7018 9036:7019 9037:7019 9038:70199039:7019 9040:7019 9041:7019 9036:7020 9037:7020 9038:7020 9039:70209040:7020 9041:7020 9036:7021 9037:7021 9038:7021 9039:7021 9040:70219041:7021 9036:7022 9037:7022 9038:7022 9039:7022 9040:7022 9041:70229036:7023 9037:7023 9038:7023 9039:7023 9040:7023 9041:7023 9036:70249037:7024 9038:7024 9039:7024 9040:7024 9041:7024 9036:7025 9037:70259038:7025 9039:7025 9040:7025 9041:7025 9036:7026 9037:7026 9038:70269039:7026 9040:7026 9041:7026 9036:7027 9037:7027 9038:7027 9039:70279040:7027 9041:7027 9042:7000 9043:7000 9044:7000 9045:7000 9046:70009047:7000 9042:7001 9043:7001 9044:7001 9045:7001 9046:7001 9047:70019042:7002 9043:7002 9044:7002 9045:7002 9046:7002 9047:7002 9042:70039043:7003 9044:7003 9045:7003 9046:7003 9047:7003 9042:7004 9043:70049044:7004 9045:7004 9046:7004 9047:7004 9042:7005 9043:7005 9044:70059045:7005 9046:7005 9047:7005 9042:7006 9043:7006 9044:7006 9045:70069046:7006 9047:7006 9042:7007 9043:7007 9044:7007 9045:7007 9046:70079047:7007 9042:7008 9043:7008 9044:7008 9045:7008 9046:7008 9047:70089042:7009 9043:7009 9044:7009 9045:7009 9046:7009 9047:7009 9042:70109043:7010 9044:7010 9045:7010 9046:7010 9047:7010 9042:7011 9043:70119044:7011 9045:7011 9046:7011 9047:7011 9042:7012 9043:7012 9044:70129045:7012 9046:7012 9047:7012 9042:7013 9043:7013 9044:7013 9045:70139046:7013 9047:7013 9042:7014 9043:7014 9044:7014 9045:7014 9046:70149047:7014 9042:7015 9043:7015 9044:7015 9045:7015 9046:7015 9047:70159042:7016 9043:7016 9044:7016 9045:7016 9046:7016 9047:7016 9042:70179043:7017 9044:7017 9045:7017 9046:7017 9047:7017 9042:7018 9043:70189044:7018 9045:7018 9046:7018 9047:7018 9042:7019 9043:7019 9044:70199045:7019 9046:7019 9047:7019 9042:7020 9043:7020 9044:7020 9045:70209046:7020 9047:7020 9042:7021 9043:7021 9044:7021 9045:7021 9046:70219047:7021 9042:7022 9043:7022 9044:7022 9045:7022 9046:7022 9047:70229042:7023 9043:7023 9044:7023 9045:7023 9046:7023 9047:7023 9042:70249043:7024 9044:7024 9045:7024 9046:7024 9047:7024 9042:7025 9043:70259044:7025 9045:7025 9046:7025 9047:7025 9042:7026 9043:7026 9044:70269045:7026 9046:7026 9047:7026 9042:7027 9043:7027 9044:7027 9045:70279046:7027 9047:7027 9048:7000 9049:7000 9050:7000 9051:7000 9052:70009053:7000 9048:7001 9049:7001 9050:7001 9051:7001 9052:7001 9053:70019048:7002 9049:7002 9050:7002 9051:7002 9052:7002 9053:7002 9048:70039049:7003 9050:7003 9051:7003 9052:7003 9053:7003 9048:7004 9049:70049050:7004 9051:7004 9052:7004 9053:7004 9048:7005 9049:7005 9050:70059051:7005 9052:7005 9053:7005 9048:7006 9049:7006 9050:7006 9051:70069052:7006 9053:7006 9048:7007 9049:7007 9050:7007 9051:7007 9052:70079053:7007 9048:7008 9049:7008 9050:7008 9051:7008 9052:7008 9053:70089048:7009 9049:7009 9050:7009 9051:7009 9052:7009 9053:7009 9048:70109049:7010 9050:7010 9051:7010 9052:7010 9053:7010 9048:7011 9049:70119050:7011 9051:7011 9052:7011 9053:7011 9048:7012 9049:7012 9050:70129051:7012 9052:7012 9053:7012 9048:7013 9049:7013 9050:7013 9051:70139052:7013 9053:7013 9048:7014 9049:7014 9050:7014 9051:7014 9052:70149053:7014 9048:7015 9049:7015 9050:7015 9051:7015 9052:7015 9053:70159048:7016 9049:7016 9050:7016 9051:7016 9052:7016 9053:7016 9048:70179049:7017 9050:7017 9051:7017 9052:7017 9053:7017 9048:7018 9049:70189050:7018 9051:7018 9052:7018 9053:7018 9048:7019 9049:7019 9050:70199051:7019 9052:7019 9053:7019 9048:7020 9049:7020 9050:7020 9051:70209052:7020 9053:7020 9048:7021 9049:7021 9050:7021 9051:7021 9052:70219053:7021 9048:7022 9049:7022 9050:7022 9051:7022 9052:7022 9053:70229048:7023 9049:7023 9050:7023 9051:7023 9052:7023 9053:7023 9048:70249049:7024 9050:7024 9051:7024 9052:7024 9053:7024 9048:7025 9049:70259050:7025 9051:7025 9052:7025 9053:7025 9048:7026 9049:7026 9050:70269051:7026 9052:7026 9053:7026 9048:7027 9049:7027 9050:7027 9051:70279052:7027 9053:7027 9054:7000 9055:7000 9056:7000 9057:7000 9058:70009059:7000 9054:7001 9055:7001 9056:7001 9057:7001 9058:7001 9059:70019054:7002 9055:7002 9056:7002 9057:7002 9058:7002 9059:7002 9054:70039055:7003 9056:7003 9057:7003 9058:7003 9059:7003 9054:7004 9055:70049056:7004 9057:7004 9058:7004 9059:7004 9054:7005 9055:7005 9056:70059057:7005 9058:7005 9059:7005 9054:7006 9055:7006 9056:7006 9057:70069058:7006 9059:7006 9054:7007 9055:7007 9056:7007 9057:7007 9058:70079059:7007 9054:7008 9055:7008 9056:7008 9057:7008 9058:7008 9059:70089054:7009 9055:7009 9056:7009 9057:7009 9058:7009 9059:7009 9054:70109055:7010 9056:7010 9057:7010 9058:7010 9059:7010 9054:7011 9055:70119056:7011 9057:7011 9058:7011 9059:7011 9054:7012 9055:7012 9056:70129057:7012 9058:7012 9059:7012 9054:7013 9055:7013 9056:7013 9057:70139058:7013 9059:7013 9054:7014 9055:7014 9056:7014 9057:7014 9058:70149059:7014 9054:7015 9055:7015 9056:7015 9057:7015 9058:7015 9059:70159054:7016 9055:7016 9056:7016 9057:7016 9058:7016 9059:7016 9054:70179055:7017 9056:7017 9057:7017 9058:7017 9059:7017 9054:7018 9055:70189056:7018 9057:7018 9058:7018 9059:7018 9054:7019 9055:7019 9056:70199057:7019 9058:7019 9059:7019 9054:7020 9055:7020 9056:7020 9057:70209058:7020 9059:7020 9054:7021 9055:7021 9056:7021 9057:7021 9058:70219059:7021 9054:7022 9055:7022 9056:7022 9057:7022 9058:7022 9059:70229054:7023 9055:7023 9056:7023 9057:7023 9058:7023 9059:7023 9054:70249055:7024 9056:7024 9057:7024 9058:7024 9059:7024 9054:7025 9055:70259056:7025 9057:7025 9058:7025 9059:7025 9054:7026 9055:7026 9056:70269057:7026 9058:7026 9059:7026 9054:7027 9055:7027 9056:7027 9057:70279058:7027 9059:7027 9060:7000 9061:7000 9062:7000 9063:7000 9064:70009065:7000 9060:7001 9061:7001 9062:7001 9063:7001 9064:7001 9065:70019060:7002 9061:7002 9062:7002 9063:7002 9064:7002 9065:7002 9060:70039061:7003 9062:7003 9063:7003 9064:7003 9065:7003 9060:7004 9061:70049062:7004 9063:7004 9064:7004 9065:7004 9060:7005 9061:7005 9062:70059063:7005 9064:7005 9065:7005 9060:7006 9061:7006 9062:7006 9063:70069064:7006 9065:7006 9060:7007 9061:7007 9062:7007 9063:7007 9064:70079065:7007 9060:7008 9061:7008 9062:7008 9063:7008 9064:7008 9065:70089060:7009 9061:7009 9062:7009 9063:7009 9064:7009 9065:7009 9060:70109061:7010 9062:7010 9063:7010 9064:7010 9065:7010 9060:7011 9061:70119062:7011 9063:7011 9064:7011 9065:7011 9060:7012 9061:7012 9062:70129063:7012 9064:7012 9065:7012 9060:7013 9061:7013 9062:7013 9063:70139064:7013 9065:7013 9060:7014 9061:7014 9062:7014 9063:7014 9064:70149065:7014 9060:7015 9061:7015 9062:7015 9063:7015 9064:7015 9065:70159060:7016 9061:7016 9062:7016 9063:7016 9064:7016 9065:7016 9060:70179061:7017 9062:7017 9063:7017 9064:7017 9065:7017 9060:7018 9061:70189062:7018 9063:7018 9064:7018 9065:7018 9060:7019 9061:7019 9062:70199063:7019 9064:7019 9065:7019 9060:7020 9061:7020 9062:7020 9063:70209064:7020 9065:7020 9060:7021 9061:7021 9062:7021 9063:7021 9064:70219065:7021 9060:7022 9061:7022 9062:7022 9063:7022 9064:7022 9065:70229060:7023 9061:7023 9062:7023 9063:7023 9064:7023 9065:7023 9060:70249061:7024 9062:7024 9063:7024 9064:7024 9065:7024 9060:7025 9061:70259062:7025 9063:7025 9064:7025 9065:7025 9060:7026 9061:7026 9062:70269063:7026 9064:7026 9065:7026 9060:7027 9061:7027 9062:7027 9063:70279064:7027 9065:7027 9066:7000 9067:7000 9068:7000 9069:7000 9070:70009071:7000 9066:7001 9067:7001 9068:7001 9069:7001 9070:7001 9071:70019066:7002 9067:7002 9068:7002 9069:7002 9070:7002 9071:7002 9066:70039067:7003 9068:7003 9069:7003 9070:7003 9071:7003 9066:7004 9067:70049068:7004 9069:7004 9070:7004 9071:7004 9066:7005 9067:7005 9068:70059069:7005 9070:7005 9071:7005 9066:7006 9067:7006 9068:7006 9069:70069070:7006 9071:7006 9066:7007 9067:7007 9068:7007 9069:7007 9070:70079071:7007 9066:7008 9067:7008 9068:7008 9069:7008 9070:7008 9071:70089066:7009 9067:7009 9068:7009 9069:7009 9070:7009 9071:7009 9066:70109067:7010 9068:7010 9069:7010 9070:7010 9071:7010 9066:7011 9067:70119068:7011 9069:7011 9070:7011 9071:7011 9066:7012 9067:7012 9068:70129069:7012 9070:7012 9071:7012 9066:7013 9067:7013 9068:7013 9069:70139070:7013 9071:7013 9066:7014 9067:7014 9068:7014 9069:7014 9070:70149071:7014 9066:7015 9067:7015 9068:7015 9069:7015 9070:7015 9071:70159066:7016 9067:7016 9068:7016 9069:7016 9070:7016 9071:7016 9066:70179067:7017 9068:7017 9069:7017 9070:7017 9071:7017 9066:7018 9067:70189068:7018 9069:7018 9070:7018 9071:7018 9066:7019 9067:7019 9068:70199069:7019 9070:7019 9071:7019 9066:7020 9067:7020 9068:7020 9069:70209070:7020 9071:7020 9066:7021 9067:7021 9068:7021 9069:7021 9070:70219071:7021 9066:7022 9067:7022 9068:7022 9069:7022 9070:7022 9071:70229066:7023 9067:7023 9068:7023 9069:7023 9070:7023 9071:7023 9066:70249067:7024 9068:7024 9069:7024 9070:7024 9071:7024 9066:7025 9067:70259068:7025 9069:7025 9070:7025 9071:7025 9066:7026 9067:7026 9068:70269069:7026 9070:7026 9071:7026 9066:7027 9067:7027 9068:7027 9069:70279070:7027 9071:7027 9072:7000 9073:7000 9074:7000 9075:7000 9076:70009077:7000 9072:7001 9073:7001 9074:7001 9075:7001 9076:7001 9077:70019072:7002 9073:7002 9074:7002 9075:7002 9076:7002 9077:7002 9072:70039073:7003 9074:7003 9075:7003 9076:7003 9077:7003 9072:7004 9073:70049074:7004 9075:7004 9076:7004 9077:7004 9072:7005 9073:7005 9074:70059075:7005 9076:7005 9077:7005 9072:7006 9073:7006 9074:7006 9075:70069076:7006 9077:7006 9072:7007 9073:7007 9074:7007 9075:7007 9076:70079077:7007 9072:7008 9073:7008 9074:7008 9075:7008 9076:7008 9077:70089072:7009 9073:7009 9074:7009 9075:7009 9076:7009 9077:7009 9072:70109073:7010 9074:7010 9075:7010 9076:7010 9077:7010 9072:7011 9073:70119074:7011 9075:7011 9076:7011 9077:7011 9072:7012 9073:7012 9074:70129075:7012 9076:7012 9077:7012 9072:7013 9073:7013 9074:7013 9075:70139076:7013 9077:7013 9072:7014 9073:7014 9074:7014 9075:7014 9076:70149077:7014 9072:7015 9073:7015 9074:7015 9075:7015 9076:7015 9077:70159072:7016 9073:7016 9074:7016 9075:7016 9076:7016 9077:7016 9072:70179073:7017 9074:7017 9075:7017 9076:7017 9077:7017 9072:7018 9073:70189074:7018 9075:7018 9076:7018 9077:7018 9072:7019 9073:7019 9074:70199075:7019 9076:7019 9077:7019 9072:7020 9073:7020 9074:7020 9075:70209076:7020 9077:7020 9072:7021 9073:7021 9074:7021 9075:7021 9076:70219077:7021 9072:7022 9073:7022 9074:7022 9075:7022 9076:7022 9077:70229072:7023 9073:7023 9074:7023 9075:7023 9076:7023 9077:7023 9072:70249073:7024 9074:7024 9075:7024 9076:7024 9077:7024 9072:7025 9073:70259074:7025 9075:7025 9076:7025 9077:7025 9072:7026 9073:7026 9074:70269075:7026 9076:7026 9077:7026 9072:7027 9073:7027 9074:7027 9075:70279076:7027 9077:7027 9078:7000 9079:7000 9080:7000 9081:7000 9082:70009083:7000 9078:7001 9079:7001 9080:7001 9081:7001 9082:7001 9083:70019078:7002 9079:7002 9080:7002 9081:7002 9082:7002 9083:7002 9078:70039079:7003 9080:7003 9081:7003 9082:7003 9083:7003 9078:7004 9079:70049080:7004 9081:7004 9082:7004 9083:7004 9078:7005 9079:7005 9080:70059081:7005 9082:7005 9083:7005 9078:7006 9079:7006 9080:7006 9081:70069082:7006 9083:7006 9078:7007 9079:7007 9080:7007 9081:7007 9082:70079083:7007 9078:7008 9079:7008 9080:7008 9081:7008 9082:7008 9083:70089078:7009 9079:7009 9080:7009 9081:7009 9082:7009 9083:7009 9078:70109079:7010 9080:7010 9081:7010 9082:7010 9083:7010 9078:7011 9079:70119080:7011 9081:7011 9082:7011 9083:7011 9078:7012 9079:7012 9080:70129081:7012 9082:7012 9083:7012 9078:7013 9079:7013 9080:7013 9081:70139082:7013 9083:7013 9078:7014 9079:7014 9080:7014 9081:7014 9082:70149083:7014 9078:7015 9079:7015 9080:7015 9081:7015 9082:7015 9083:70159078:7016 9079:7016 9080:7016 9081:7016 9082:7016 9083:7016 9078:70179079:7017 9080:7017 9081:7017 9082:7017 9083:7017 9078:7018 9079:70189080:7018 9081:7018 9082:7018 9083:7018 9078:7019 9079:7019 9080:70199081:7019 9082:7019 9083:7019 9078:7020 9079:7020 9080:7020 9081:70209082:7020 9083:7020 9078:7021 9079:7021 9080:7021 9081:7021 9082:70219083:7021 9078:7022 9079:7022 9080:7022 9081:7022 9082:7022 9083:70229078:7023 9079:7023 9080:7023 9081:7023 9082:7023 9083:7023 9078:70249079:7024 9080:7024 9081:7024 9082:7024 9083:7024 9078:7025 9079:70259080:7025 9081:7025 9082:7025 9083:7025 9078:7026 9079:7026 9080:70269081:7026 9082:7026 9083:7026 9078:7027 9079:7027 9080:7027 9081:70279082:7027 9083:7027 9084:7000 9085:7000 9086:7000 9087:7000 9088:70009089:7000 9084:7001 9085:7001 9086:7001 9087:7001 9088:7001 9089:70019084:7002 9085:7002 9086:7002 9087:7002 9088:7002 9089:7002 9084:70039085:7003 9086:7003 9087:7003 9088:7003 9089:7003 9084:7004 9085:70049086:7004 9087:7004 9088:7004 9089:7004 9084:7005 9085:7005 9086:70059087:7005 9088:7005 9089:7005 9084:7006 9085:7006 9086:7006 9087:70069088:7006 9089:7006 9084:7007 9085:7007 9086:7007 9087:7007 9088:70079089:7007 9084:7008 9085:7008 9086:7008 9087:7008 9088:7008 9089:70089084:7009 9085:7009 9086:7009 9087:7009 9088:7009 9089:7009 9084:70109085:7010 9086:7010 9087:7010 9088:7010 9089:7010 9084:7011 9085:70119086:7011 9087:7011 9088:7011 9089:7011 9084:7012 9085:7012 9086:70129087:7012 9088:7012 9089:7012 9084:7013 9085:7013 9086:7013 9087:70139088:7013 9089:7013 9084:7014 9085:7014 9086:7014 9087:7014 9088:70149089:7014 9084:7015 9085:7015 9086:7015 9087:7015 9088:7015 9089:70159084:7016 9085:7016 9086:7016 9087:7016 9088:7016 9089:7016 9084:70179085:7017 9086:7017 9087:7017 9088:7017 9089:7017 9084:7018 9085:70189086:7018 9087:7018 9088:7018 9089:7018 9084:7019 9085:7019 9086:70199087:7019 9088:7019 9089:7019 9084:7020 9085:7020 9086:7020 9087:70209088:7020 9089:7020 9084:7021 9085:7021 9086:7021 9087:7021 9088:70219089:7021 9084:7022 9085:7022 9086:7022 9087:7022 9088:7022 9089:70229084:7023 9085:7023 9086:7023 9087:7023 9088:7023 9089:7023 9084:70249085:7024 9086:7024 9087:7024 9088:7024 9089:7024 9084:7025 9085:70259086:7025 9087:7025 9088:7025 9089:7025 9084:7026 9085:7026 9086:70269087:7026 9088:7026 9089:7026 9084:7027 9085:7027 9086:7027 9087:70279088:7027 9089:7027 9090:7000 9091:7000 9092:7000 9093:7000 9094:70009095:7000 9090:7001 9091:7001 9092:7001 9093:7001 9094:7001 9095:70019090:7002 9091:7002 9092:7002 9093:7002 9094:7002 9095:7002 9090:70039091:7003 9092:7003 9093:7003 9094:7003 9095:7003 9090:7004 9091:70049092:7004 9093:7004 9094:7004 9095:7004 9090:7005 9091:7005 9092:70059093:7005 9094:7005 9095:7005 9090:7006 9091:7006 9092:7006 9093:70069094:7006 9095:7006 9090:7007 9091:7007 9092:7007 9093:7007 9094:70079095:7007 9090:7008 9091:7008 9092:7008 9093:7008 9094:7008 9095:70089090:7009 9091:7009 9092:7009 9093:7009 9094:7009 9095:7009 9090:70109091:7010 9092:7010 9093:7010 9094:7010 9095:7010 9090:7011 9091:70119092:7011 9093:7011 9094:7011 9095:7011 9090:7012 9091:7012 9092:70129093:7012 9094:7012 9095:7012 9090:7013 9091:7013 9092:7013 9093:70139094:7013 9095:7013 9090:7014 9091:7014 9092:7014 9093:7014 9094:70149095:7014 9090:7015 9091:7015 9092:7015 9093:7015 9094:7015 9095:70159090:7016 9091:7016 9092:7016 9093:7016 9094:7016 9095:7016 9090:70179091:7017 9092:7017 9093:7017 9094:7017 9095:7017 9090:7018 9091:70189092:7018 9093:7018 9094:7018 9095:7018 9090:7019 9091:7019 9092:70199093:7019 9094:7019 9095:7019 9090:7020 9091:7020 9092:7020 9093:70209094:7020 9095:7020 9090:7021 9091:7021 9092:7021 9093:7021 9094:70219095:7021 9090:7022 9091:7022 9092:7022 9093:7022 9094:7022 9095:70229090:7023 9091:7023 9092:7023 9093:7023 9094:7023 9095:7023 9090:70249091:7024 9092:7024 9093:7024 9094:7024 9095:7024 9090:7025 9091:70259092:7025 9093:7025 9094:7025 9095:7025 9090:7026 9091:7026 9092:70269093:7026 9094:7026 9095:7026 9090:7027 9091:7027 9092:7027 9093:70279094:7027 9095:7027 9096:7000 9097:7000 9098:7000 9099:7000 9100:70009101:7000 9096:7001 9097:7001 9098:7001 9099:7001 9100:7001 9101:70019096:7002 9097:7002 9098:7002 9099:7002 9100:7002 9101:7002 9096:70039097:7003 9098:7003 9099:7003 9100:7003 9101:7003 9096:7004 9097:70049098:7004 9099:7004 9100:7004 9101:7004 9096:7005 9097:7005 9098:70059099:7005 9100:7005 9101:7005 9096:7006 9097:7006 9098:7006 9099:70069100:7006 9101:7006 9096:7007 9097:7007 9098:7007 9099:7007 9100:70079101:7007 9096:7008 9097:7008 9098:7008 9099:7008 9100:7008 9101:70089096:7009 9097:7009 9098:7009 9099:7009 9100:7009 9101:7009 9096:70109097:7010 9098:7010 9099:7010 9100:7010 9101:7010 9096:7011 9097:70119098:7011 9099:7011 9100:7011 9101:7011 9096:7012 9097:7012 9098:70129099:7012 9100:7012 9101:7012 9096:7013 9097:7013 9098:7013 9099:70139100:7013 9101:7013 9096:7014 9097:7014 9098:7014 9099:7014 9100:70149101:7014 9096:7015 9097:7015 9098:7015 9099:7015 9100:7015 9101:70159096:7016 9097:7016 9098:7016 9099:7016 9100:7016 9101:7016 9096:70179097:7017 9098:7017 9099:7017 9100:7017 9101:7017 9096:7018 9097:70189098:7018 9099:7018 9100:7018 9101:7018 9096:7019 9097:7019 9098:70199099:7019 9100:7019 9101:7019 9096:7020 9097:7020 9098:7020 9099:70209100:7020 9101:7020 9096:7021 9097:7021 9098:7021 9099:7021 9100:70219101:7021 9096:7022 9097:7022 9098:7022 9099:7022 9100:7022 9101:70229096:7023 9097:7023 9098:7023 9099:7023 9100:7023 9101:7023 9096:70249097:7024 9098:7024 9099:7024 9100:7024 9101:7024 9096:7025 9097:70259098:7025 9099:7025 9100:7025 9101:7025 9096:7026 9097:7026 9098:70269099:7026 9100:7026 9101:7026 9096:7027 9097:7027 9098:7027 9099:70279100:7027 9101:7027 9102:7000 9103:7000 9104:7000 9105:7000 — —9102:7001 9103:7001 9104:7001 9105:7001 9102:7002 9103:7002 9104:70029105:7002 9102:7003 9103:7003 9104:7003 9105:7003 9102:7004 9103:70049104:7004 9105:7004 9102:7005 9103:7005 9104:7005 9105:7005 9102:70069103:7006 9104:7006 9105:7006 9102:7007 9103:7007 9104:7007 9105:70079102:7008 9103:7008 9104:7008 9105:7008 9102:7009 9103:7009 9104:70099105:7009 9102:7010 9103:7010 9104:7010 9105:7010 9102:7011 9103:70119104:7011 9105:7011 9102:7012 9103:7012 9104:7012 9105:7012 9102:70139103:7013 9104:7013 9105:7013 9102:7014 9103:7014 9104:7014 9105:70149102:7015 9103:7015 9104:7015 9105:7015 9102:7016 9103:7016 9104:70169105:7016 9102:7017 9103:7017 9104:7017 9105:7017 9102:7018 9103:70189104:7018 9105:7018 9102:7019 9103:7019 9104:7019 9105:7019 9102:70209103:7020 9104:7020 9105:7020 9102:7021 9103:7021 9104:7021 9105:70219102:7022 9103:7022 9104:7022 9105:7022 9102:7023 9103:7023 9104:70239105:7023 9102:7024 9103:7024 9104:7024 9105:7024 9102:7025 9103:70259104:7025 9105:7025 9102:7026 9103:7026 9104:7026 9105:7026 9102:70279103:7027 9104:7027 9105:7027

TABLE D Example combinations of a compound X with a compound Y. X:Y X:YX:Y X:Y X:Y X:Y 6000:9000 6040:9000 6000:9001 6040:9001 6000:90026040:9002 6001:9000 6041:9000 6001:9001 6041:9001 6001:9002 6041:90026002:9000 6042:9000 6002:9001 6042:9001 6002:9002 6042:9002 6003:90006043:9000 6003:9001 6043:9001 6003:9002 6043:9002 6004:9000 6044:90006004:9001 6044:9001 6004:9002 6044:9002 6005:9000 6045:9000 6005:90016045:9001 6005:9002 6045:9002 6006:9000 6046:9000 6006:9001 6046:90016006:9002 6046:9002 6007:9000 6047:9000 6007:9001 6047:9001 6007:90026047:9002 6008:9000 6048:9000 6008:9001 6048:9001 6008:9002 6048:90026009:9000 6049:9000 6009:9001 6049:9001 6009:9002 6049:9002 6010:90006050:9000 6010:9001 6050:9001 6010:9002 6050:9002 6011:9000 6051:90006011:9001 6051:9001 6011:9002 6051:9002 6012:9000 6052:9000 6012:90016052:9001 6012:9002 6052:9002 6013:9000 6053:9000 6013:9001 6053:90016013:9002 6053:9002 6014:9000 6054:9000 6014:9001 6054:9001 6014:90026054:9002 6015:9000 6055:9000 6015:9001 6055:9001 6015:9002 6055:90026016:9000 6056:9000 6016:9001 6056:9001 6016:9002 6056:9002 6017:90006057:9000 6017:9001 6057:9001 6017:9002 6057:9002 6018:9000 6058:90006018:9001 6058:9001 6018:9002 6058:9002 6019:9000 6059:9000 6019:90016059:9001 6019:9002 6059:9002 6020:9000 6060:9000 6020:9001 6060:90016020:9002 6060:9002 6021:9000 6061:9000 6021:9001 6061:9001 6021:90026061:9002 6022:9000 6062:9000 6022:9001 6062:9001 6022:9002 6062:90026023:9000 6063:9000 6023:9001 6063:9001 6023:9002 6063:9002 6024:90006064:9000 6024:9001 6064:9001 6024:9002 6064:9002 6025:9000 6065:90006025:9001 6065:9001 6025:9002 6065:9002 6026:9000 6066:9000 6026:90016066:9001 6026:9002 6066:9002 6027:9000 6067:9000 6027:9001 6067:90016027:9002 6067:9002 6028:9000 6068:9000 6028:9001 6068:9001 6028:90026068:9002 6029:9000 6069:9000 6029:9001 6069:9001 6029:9002 6069:90026030:9000 6070:9000 6030:9001 6070:9001 6030:9002 6070:9002 6031:90006071:9000 6031:9001 6071:9001 6031:9002 6071:9002 6032:9000 6072:90006032:9001 6072:9001 6032:9002 6072:9002 6033:9000 6073:9000 6033:90016073:9001 6033:9002 6073:9002 6034:9000 6074:9000 6034:9001 6074:90016034:9002 6074:9002 6035:9000 6075:9000 6035:9001 6075:9001 6035:90026075:9002 6036:9000 6076:9000 6036:9001 6076:9001 6036:9002 6076:90026037:9000 6077:9000 6037:9001 6077:9001 6037:9002 6077:9002 6038:90006078:9000 6038:9001 6078:9001 6038:9002 6078:9002 6039:9000 6039:90016039:9002 6000:9003 6040:9003 6000:9004 6040:9004 6000:9005 6040:90056001:9003 6041:9003 6001:9004 6041:9004 6001:9005 6041:9005 6002:90036042:9003 6002:9004 6042:9004 6002:9005 6042:9005 6003:9003 6043:90036003:9004 6043:9004 6003:9005 6043:9005 6004:9003 6044:9003 6004:90046044:9004 6004:9005 6044:9005 6005:9003 6045:9003 6005:9004 6045:90046005:9005 6045:9005 6006:9003 6046:9003 6006:9004 6046:9004 6006:90056046:9005 6007:9003 6047:9003 6007:9004 6047:9004 6007:9005 6047:90056008:9003 6048:9003 6008:9004 6048:9004 6008:9005 6048:9005 6009:90036049:9003 6009:9004 6049:9004 6009:9005 6049:9005 6010:9003 6050:90036010:9004 6050:9004 6010:9005 6050:9005 6011:9003 6051:9003 6011:90046051:9004 6011:9005 6051:9005 6012:9003 6052:9003 6012:9004 6052:90046012:9005 6052:9005 6013:9003 6053:9003 6013:9004 6053:9004 6013:90056053:9005 6014:9003 6054:9003 6014:9004 6054:9004 6014:9005 6054:90056015:9003 6055:9003 6015:9004 6055:9004 6015:9005 6055:9005 6016:90036056:9003 6016:9004 6056:9004 6016:9005 6056:9005 6017:9003 6057:90036017:9004 6057:9004 6017:9005 6057:9005 6018:9003 6058:9003 6018:90046058:9004 6018:9005 6058:9005 6019:9003 6059:9003 6019:9004 6059:90046019:9005 6059:9005 6020:9003 6060:9003 6020:9004 6060:9004 6020:90056060:9005 6021:9003 6061:9003 6021:9004 6061:9004 6021:9005 6061:90056022:9003 6062:9003 6022:9004 6062:9004 6022:9005 6062:9005 6023:90036063:9003 6023:9004 6063:9004 6023:9005 6063:9005 6024:9003 6064:90036024:9004 6064:9004 6024:9005 6064:9005 6025:9003 6065:9003 6025:90046065:9004 6025:9005 6065:9005 6026:9003 6066:9003 6026:9004 6066:90046026:9005 6066:9005 6027:9003 6067:9003 6027:9004 6067:9004 6027:90056067:9005 6028:9003 6068:9003 6028:9004 6068:9004 6028:9005 6068:90056029:9003 6069:9003 6029:9004 6069:9004 6029:9005 6069:9005 6030:90036070:9003 6030:9004 6070:9004 6030:9005 6070:9005 6031:9003 6071:90036031:9004 6071:9004 6031:9005 6071:9005 6032:9003 6072:9003 6032:90046072:9004 6032:9005 6072:9005 6033:9003 6073:9003 6033:9004 6073:90046033:9005 6073:9005 6034:9003 6074:9003 6034:9004 6074:9004 6034:90056074:9005 6035:9003 6075:9003 6035:9004 6075:9004 6035:9005 6075:90056036:9003 6076:9003 6036:9004 6076:9004 6036:9005 6076:9005 6037:90036077:9003 6037:9004 6077:9004 6037:9005 6077:9005 6038:9003 6078:90036038:9004 6078:9004 6038:9005 6078:9005 6039:9003 6039:9004 6039:90056000:9006 6040:9006 6000:9007 6040:9007 6000:9008 6040:9008 6001:90066041:9006 6001:9007 6041:9007 6001:9008 6041:9008 6002:9006 6042:90066002:9007 6042:9007 6002:9008 6042:9008 6003:9006 6043:9006 6003:90076043:9007 6003:9008 6043:9008 6004:9006 6044:9006 6004:9007 6044:90076004:9008 6044:9008 6005:9006 6045:9006 6005:9007 6045:9007 6005:90086045:9008 6006:9006 6046:9006 6006:9007 6046:9007 6006:9008 6046:90086007:9006 6047:9006 6007:9007 6047:9007 6007:9008 6047:9008 6008:90066048:9006 6008:9007 6048:9007 6008:9008 6048:9008 6009:9006 6049:90066009:9007 6049:9007 6009:9008 6049:9008 6010:9006 6050:9006 6010:90076050:9007 6010:9008 6050:9008 6011:9006 6051:9006 6011:9007 6051:90076011:9008 6051:9008 6012:9006 6052:9006 6012:9007 6052:9007 6012:90086052:9008 6013:9006 6053:9006 6013:9007 6053:9007 6013:9008 6053:90086014:9006 6054:9006 6014:9007 6054:9007 6014:9008 6054:9008 6015:90066055:9006 6015:9007 6055:9007 6015:9008 6055:9008 6016:9006 6056:90066016:9007 6056:9007 6016:9008 6056:9008 6017:9006 6057:9006 6017:90076057:9007 6017:9008 6057:9008 6018:9006 6058:9006 6018:9007 6058:90076018:9008 6058:9008 6019:9006 6059:9006 6019:9007 6059:9007 6019:90086059:9008 6020:9006 6060:9006 6020:9007 6060:9007 6020:9008 6060:90086021:9006 6061:9006 6021:9007 6061:9007 6021:9008 6061:9008 6022:90066062:9006 6022:9007 6062:9007 6022:9008 6062:9008 6023:9006 6063:90066023:9007 6063:9007 6023:9008 6063:9008 6024:9006 6064:9006 6024:90076064:9007 6024:9008 6064:9008 6025:9006 6065:9006 6025:9007 6065:90076025:9008 6065:9008 6026:9006 6066:9006 6026:9007 6066:9007 6026:90086066:9008 6027:9006 6067:9006 6027:9007 6067:9007 6027:9008 6067:90086028:9006 6068:9006 6028:9007 6068:9007 6028:9008 6068:9008 6029:90066069:9006 6029:9007 6069:9007 6029:9008 6069:9008 6030:9006 6070:90066030:9007 6070:9007 6030:9008 6070:9008 6031:9006 6071:9006 6031:90076071:9007 6031:9008 6071:9008 6032:9006 6072:9006 6032:9007 6072:90076032:9008 6072:9008 6033:9006 6073:9006 6033:9007 6073:9007 6033:90086073:9008 6034:9006 6074:9006 6034:9007 6074:9007 6034:9008 6074:90086035:9006 6075:9006 6035:9007 6075:9007 6035:9008 6075:9008 6036:90066076:9006 6036:9007 6076:9007 6036:9008 6076:9008 6037:9006 6077:90066037:9007 6077:9007 6037:9008 6077:9008 6038:9006 6078:9006 6038:90076078:9007 6038:9008 6078:9008 6039:9006 6039:9007 6039:9008 6000:90096040:9009 6000:9010 6040:9010 6000:9011 6040:9011 6001:9009 6041:90096001:9010 6041:9010 6001:9011 6041:9011 6002:9009 6042:9009 6002:90106042:9010 6002:9011 6042:9011 6003:9009 6043:9009 6003:9010 6043:90106003:9011 6043:9011 6004:9009 6044:9009 6004:9010 6044:9010 6004:90116044:9011 6005:9009 6045:9009 6005:9010 6045:9010 6005:9011 6045:90116006:9009 6046:9009 6006:9010 6046:9010 6006:9011 6046:9011 6007:90096047:9009 6007:9010 6047:9010 6007:9011 6047:9011 6008:9009 6048:90096008:9010 6048:9010 6008:9011 6048:9011 6009:9009 6049:9009 6009:90106049:9010 6009:9011 6049:9011 6010:9009 6050:9009 6010:9010 6050:90106010:9011 6050:9011 6011:9009 6051:9009 6011:9010 6051:9010 6011:90116051:9011 6012:9009 6052:9009 6012:9010 6052:9010 6012:9011 6052:90116013:9009 6053:9009 6013:9010 6053:9010 6013:9011 6053:9011 6014:90096054:9009 6014:9010 6054:9010 6014:9011 6054:9011 6015:9009 6055:90096015:9010 6055:9010 6015:9011 6055:9011 6016:9009 6056:9009 6016:90106056:9010 6016:9011 6056:9011 6017:9009 6057:9009 6017:9010 6057:90106017:9011 6057:9011 6018:9009 6058:9009 6018:9010 6058:9010 6018:90116058:9011 6019:9009 6059:9009 6019:9010 6059:9010 6019:9011 6059:90116020:9009 6060:9009 6020:9010 6060:9010 6020:9011 6060:9011 6021:90096061:9009 6021:9010 6061:9010 6021:9011 6061:9011 6022:9009 6062:90096022:9010 6062:9010 6022:9011 6062:9011 6023:9009 6063:9009 6023:90106063:9010 6023:9011 6063:9011 6024:9009 6064:9009 6024:9010 6064:90106024:9011 6064:9011 6025:9009 6065:9009 6025:9010 6065:9010 6025:90116065:9011 6026:9009 6066:9009 6026:9010 6066:9010 6026:9011 6066:90116027:9009 6067:9009 6027:9010 6067:9010 6027:9011 6067:9011 6028:90096068:9009 6028:9010 6068:9010 6028:9011 6068:9011 6029:9009 6069:90096029:9010 6069:9010 6029:9011 6069:9011 6030:9009 6070:9009 6030:90106070:9010 6030:9011 6070:9011 6031:9009 6071:9009 6031:9010 6071:90106031:9011 6071:9011 6032:9009 6072:9009 6032:9010 6072:9010 6032:90116072:9011 6033:9009 6073:9009 6033:9010 6073:9010 6033:9011 6073:90116034:9009 6074:9009 6034:9010 6074:9010 6034:9011 6074:9011 6035:90096075:9009 6035:9010 6075:9010 6035:9011 6075:9011 6036:9009 6076:90096036:9010 6076:9010 6036:9011 6076:9011 6037:9009 6077:9009 6037:90106077:9010 6037:9011 6077:9011 6038:9009 6078:9009 6038:9010 6078:90106038:9011 6078:9011 6039:9009 6039:9010 6039:9011 6000:9012 6040:90126000:9013 6040:9013 6000:9014 6040:9014 6001:9012 6041:9012 6001:90136041:9013 6001:9014 6041:9014 6002:9012 6042:9012 6002:9013 6042:90136002:9014 6042:9014 6003:9012 6043:9012 6003:9013 6043:9013 6003:90146043:9014 6004:9012 6044:9012 6004:9013 6044:9013 6004:9014 6044:90146005:9012 6045:9012 6005:9013 6045:9013 6005:9014 6045:9014 6006:90126046:9012 6006:9013 6046:9013 6006:9014 6046:9014 6007:9012 6047:90126007:9013 6047:9013 6007:9014 6047:9014 6008:9012 6048:9012 6008:90136048:9013 6008:9014 6048:9014 6009:9012 6049:9012 6009:9013 6049:90136009:9014 6049:9014 6010:9012 6050:9012 6010:9013 6050:9013 6010:90146050:9014 6011:9012 6051:9012 6011:9013 6051:9013 6011:9014 6051:90146012:9012 6052:9012 6012:9013 6052:9013 6012:9014 6052:9014 6013:90126053:9012 6013:9013 6053:9013 6013:9014 6053:9014 6014:9012 6054:90126014:9013 6054:9013 6014:9014 6054:9014 6015:9012 6055:9012 6015:90136055:9013 6015:9014 6055:9014 6016:9012 6056:9012 6016:9013 6056:90136016:9014 6056:9014 6017:9012 6057:9012 6017:9013 6057:9013 6017:90146057:9014 6018:9012 6058:9012 6018:9013 6058:9013 6018:9014 6058:90146019:9012 6059:9012 6019:9013 6059:9013 6019:9014 6059:9014 6020:90126060:9012 6020:9013 6060:9013 6020:9014 6060:9014 6021:9012 6061:90126021:9013 6061:9013 6021:9014 6061:9014 6022:9012 6062:9012 6022:90136062:9013 6022:9014 6062:9014 6023:9012 6063:9012 6023:9013 6063:90136023:9014 6063:9014 6024:9012 6064:9012 6024:9013 6064:9013 6024:90146064:9014 6025:9012 6065:9012 6025:9013 6065:9013 6025:9014 6065:90146026:9012 6066:9012 6026:9013 6066:9013 6026:9014 6066:9014 6027:90126067:9012 6027:9013 6067:9013 6027:9014 6067:9014 6028:9012 6068:90126028:9013 6068:9013 6028:9014 6068:9014 6029:9012 6069:9012 6029:90136069:9013 6029:9014 6069:9014 6030:9012 6070:9012 6030:9013 6070:90136030:9014 6070:9014 6031:9012 6071:9012 6031:9013 6071:9013 6031:90146071:9014 6032:9012 6072:9012 6032:9013 6072:9013 6032:9014 6072:90146033:9012 6073:9012 6033:9013 6073:9013 6033:9014 6073:9014 6034:90126074:9012 6034:9013 6074:9013 6034:9014 6074:9014 6035:9012 6075:90126035:9013 6075:9013 6035:9014 6075:9014 6036:9012 6076:9012 6036:90136076:9013 6036:9014 6076:9014 6037:9012 6077:9012 6037:9013 6077:90136037:9014 6077:9014 6038:9012 6078:9012 6038:9013 6078:9013 6038:90146078:9014 6039:9012 6039:9013 6039:9014 6000:9015 6040:9015 6000:90166040:9016 6000:9017 6040:9017 6001:9015 6041:9015 6001:9016 6041:90166001:9017 6041:9017 6002:9015 6042:9015 6002:9016 6042:9016 6002:90176042:9017 6003:9015 6043:9015 6003:9016 6043:9016 6003:9017 6043:90176004:9015 6044:9015 6004:9016 6044:9016 6004:9017 6044:9017 6005:90156045:9015 6005:9016 6045:9016 6005:9017 6045:9017 6006:9015 6046:90156006:9016 6046:9016 6006:9017 6046:9017 6007:9015 6047:9015 6007:90166047:9016 6007:9017 6047:9017 6008:9015 6048:9015 6008:9016 6048:90166008:9017 6048:9017 6009:9015 6049:9015 6009:9016 6049:9016 6009:90176049:9017 6010:9015 6050:9015 6010:9016 6050:9016 6010:9017 6050:90176011:9015 6051:9015 6011:9016 6051:9016 6011:9017 6051:9017 6012:90156052:9015 6012:9016 6052:9016 6012:9017 6052:9017 6013:9015 6053:90156013:9016 6053:9016 6013:9017 6053:9017 6014:9015 6054:9015 6014:90166054:9016 6014:9017 6054:9017 6015:9015 6055:9015 6015:9016 6055:90166015:9017 6055:9017 6016:9015 6056:9015 6016:9016 6056:9016 6016:90176056:9017 6017:9015 6057:9015 6017:9016 6057:9016 6017:9017 6057:90176018:9015 6058:9015 6018:9016 6058:9016 6018:9017 6058:9017 6019:90156059:9015 6019:9016 6059:9016 6019:9017 6059:9017 6020:9015 6060:90156020:9016 6060:9016 6020:9017 6060:9017 6021:9015 6061:9015 6021:90166061:9016 6021:9017 6061:9017 6022:9015 6062:9015 6022:9016 6062:90166022:9017 6062:9017 6023:9015 6063:9015 6023:9016 6063:9016 6023:90176063:9017 6024:9015 6064:9015 6024:9016 6064:9016 6024:9017 6064:90176025:9015 6065:9015 6025:9016 6065:9016 6025:9017 6065:9017 6026:90156066:9015 6026:9016 6066:9016 6026:9017 6066:9017 6027:9015 6067:90156027:9016 6067:9016 6027:9017 6067:9017 6028:9015 6068:9015 6028:90166068:9016 6028:9017 6068:9017 6029:9015 6069:9015 6029:9016 6069:90166029:9017 6069:9017 6030:9015 6070:9015 6030:9016 6070:9016 6030:90176070:9017 6031:9015 6071:9015 6031:9016 6071:9016 6031:9017 6071:90176032:9015 6072:9015 6032:9016 6072:9016 6032:9017 6072:9017 6033:90156073:9015 6033:9016 6073:9016 6033:9017 6073:9017 6034:9015 6074:90156034:9016 6074:9016 6034:9017 6074:9017 6035:9015 6075:9015 6035:90166075:9016 6035:9017 6075:9017 6036:9015 6076:9015 6036:9016 6076:90166036:9017 6076:9017 6037:9015 6077:9015 6037:9016 6077:9016 6037:90176077:9017 6038:9015 6078:9015 6038:9016 6078:9016 6038:9017 6078:90176039:9015 6039:9016 6039:9017 6000:9018 6040:9018 6000:9019 6040:90196000:9020 6040:9020 6001:9018 6041:9018 6001:9019 6041:9019 6001:90206041:9020 6002:9018 6042:9018 6002:9019 6042:9019 6002:9020 6042:90206003:9018 6043:9018 6003:9019 6043:9019 6003:9020 6043:9020 6004:90186044:9018 6004:9019 6044:9019 6004:9020 6044:9020 6005:9018 6045:90186005:9019 6045:9019 6005:9020 6045:9020 6006:9018 6046:9018 6006:90196046:9019 6006:9020 6046:9020 6007:9018 6047:9018 6007:9019 6047:90196007:9020 6047:9020 6008:9018 6048:9018 6008:9019 6048:9019 6008:90206048:9020 6009:9018 6049:9018 6009:9019 6049:9019 6009:9020 6049:90206010:9018 6050:9018 6010:9019 6050:9019 6010:9020 6050:9020 6011:90186051:9018 6011:9019 6051:9019 6011:9020 6051:9020 6012:9018 6052:90186012:9019 6052:9019 6012:9020 6052:9020 6013:9018 6053:9018 6013:90196053:9019 6013:9020 6053:9020 6014:9018 6054:9018 6014:9019 6054:90196014:9020 6054:9020 6015:9018 6055:9018 6015:9019 6055:9019 6015:90206055:9020 6016:9018 6056:9018 6016:9019 6056:9019 6016:9020 6056:90206017:9018 6057:9018 6017:9019 6057:9019 6017:9020 6057:9020 6018:90186058:9018 6018:9019 6058:9019 6018:9020 6058:9020 6019:9018 6059:90186019:9019 6059:9019 6019:9020 6059:9020 6020:9018 6060:9018 6020:90196060:9019 6020:9020 6060:9020 6021:9018 6061:9018 6021:9019 6061:90196021:9020 6061:9020 6022:9018 6062:9018 6022:9019 6062:9019 6022:90206062:9020 6023:9018 6063:9018 6023:9019 6063:9019 6023:9020 6063:90206024:9018 6064:9018 6024:9019 6064:9019 6024:9020 6064:9020 6025:90186065:9018 6025:9019 6065:9019 6025:9020 6065:9020 6026:9018 6066:90186026:9019 6066:9019 6026:9020 6066:9020 6027:9018 6067:9018 6027:90196067:9019 6027:9020 6067:9020 6028:9018 6068:9018 6028:9019 6068:90196028:9020 6068:9020 6029:9018 6069:9018 6029:9019 6069:9019 6029:90206069:9020 6030:9018 6070:9018 6030:9019 6070:9019 6030:9020 6070:90206031:9018 6071:9018 6031:9019 6071:9019 6031:9020 6071:9020 6032:90186072:9018 6032:9019 6072:9019 6032:9020 6072:9020 6033:9018 6073:90186033:9019 6073:9019 6033:9020 6073:9020 6034:9018 6074:9018 6034:90196074:9019 6034:9020 6074:9020 6035:9018 6075:9018 6035:9019 6075:90196035:9020 6075:9020 6036:9018 6076:9018 6036:9019 6076:9019 6036:90206076:9020 6037:9018 6077:9018 6037:9019 6077:9019 6037:9020 6077:90206038:9018 6078:9018 6038:9019 6078:9019 6038:9020 6078:9020 6039:90186039:9019 6039:9020 6000:9021 6040:9021 6000:9022 6040:9022 6000:90236040:9023 6001:9021 6041:9021 6001:9022 6041:9022 6001:9023 6041:90236002:9021 6042:9021 6002:9022 6042:9022 6002:9023 6042:9023 6003:90216043:9021 6003:9022 6043:9022 6003:9023 6043:9023 6004:9021 6044:90216004:9022 6044:9022 6004:9023 6044:9023 6005:9021 6045:9021 6005:90226045:9022 6005:9023 6045:9023 6006:9021 6046:9021 6006:9022 6046:90226006:9023 6046:9023 6007:9021 6047:9021 6007:9022 6047:9022 6007:90236047:9023 6008:9021 6048:9021 6008:9022 6048:9022 6008:9023 6048:90236009:9021 6049:9021 6009:9022 6049:9022 6009:9023 6049:9023 6010:90216050:9021 6010:9022 6050:9022 6010:9023 6050:9023 6011:9021 6051:90216011:9022 6051:9022 6011:9023 6051:9023 6012:9021 6052:9021 6012:90226052:9022 6012:9023 6052:9023 6013:9021 6053:9021 6013:9022 6053:90226013:9023 6053:9023 6014:9021 6054:9021 6014:9022 6054:9022 6014:90236054:9023 6015:9021 6055:9021 6015:9022 6055:9022 6015:9023 6055:90236016:9021 6056:9021 6016:9022 6056:9022 6016:9023 6056:9023 6017:90216057:9021 6017:9022 6057:9022 6017:9023 6057:9023 6018:9021 6058:90216018:9022 6058:9022 6018:9023 6058:9023 6019:9021 6059:9021 6019:90226059:9022 6019:9023 6059:9023 6020:9021 6060:9021 6020:9022 6060:90226020:9023 6060:9023 6021:9021 6061:9021 6021:9022 6061:9022 6021:90236061:9023 6022:9021 6062:9021 6022:9022 6062:9022 6022:9023 6062:90236023:9021 6063:9021 6023:9022 6063:9022 6023:9023 6063:9023 6024:90216064:9021 6024:9022 6064:9022 6024:9023 6064:9023 6025:9021 6065:90216025:9022 6065:9022 6025:9023 6065:9023 6026:9021 6066:9021 6026:90226066:9022 6026:9023 6066:9023 6027:9021 6067:9021 6027:9022 6067:90226027:9023 6067:9023 6028:9021 6068:9021 6028:9022 6068:9022 6028:90236068:9023 6029:9021 6069:9021 6029:9022 6069:9022 6029:9023 6069:90236030:9021 6070:9021 6030:9022 6070:9022 6030:9023 6070:9023 6031:90216071:9021 6031:9022 6071:9022 6031:9023 6071:9023 6032:9021 6072:90216032:9022 6072:9022 6032:9023 6072:9023 6033:9021 6073:9021 6033:90226073:9022 6033:9023 6073:9023 6034:9021 6074:9021 6034:9022 6074:90226034:9023 6074:9023 6035:9021 6075:9021 6035:9022 6075:9022 6035:90236075:9023 6036:9021 6076:9021 6036:9022 6076:9022 6036:9023 6076:90236037:9021 6077:9021 6037:9022 6077:9022 6037:9023 6077:9023 6038:90216078:9021 6038:9022 6078:9022 6038:9023 6078:9023 6039:9021 6039:90226039:9023 6000:9024 6040:9024 6000:9025 6040:9025 6000:9026 6040:90266001:9024 6041:9024 6001:9025 6041:9025 6001:9026 6041:9026 6002:90246042:9024 6002:9025 6042:9025 6002:9026 6042:9026 6003:9024 6043:90246003:9025 6043:9025 6003:9026 6043:9026 6004:9024 6044:9024 6004:90256044:9025 6004:9026 6044:9026 6005:9024 6045:9024 6005:9025 6045:90256005:9026 6045:9026 6006:9024 6046:9024 6006:9025 6046:9025 6006:90266046:9026 6007:9024 6047:9024 6007:9025 6047:9025 6007:9026 6047:90266008:9024 6048:9024 6008:9025 6048:9025 6008:9026 6048:9026 6009:90246049:9024 6009:9025 6049:9025 6009:9026 6049:9026 6010:9024 6050:90246010:9025 6050:9025 6010:9026 6050:9026 6011:9024 6051:9024 6011:90256051:9025 6011:9026 6051:9026 6012:9024 6052:9024 6012:9025 6052:90256012:9026 6052:9026 6013:9024 6053:9024 6013:9025 6053:9025 6013:90266053:9026 6014:9024 6054:9024 6014:9025 6054:9025 6014:9026 6054:90266015:9024 6055:9024 6015:9025 6055:9025 6015:9026 6055:9026 6016:90246056:9024 6016:9025 6056:9025 6016:9026 6056:9026 6017:9024 6057:90246017:9025 6057:9025 6017:9026 6057:9026 6018:9024 6058:9024 6018:90256058:9025 6018:9026 6058:9026 6019:9024 6059:9024 6019:9025 6059:90256019:9026 6059:9026 6020:9024 6060:9024 6020:9025 6060:9025 6020:90266060:9026 6021:9024 6061:9024 6021:9025 6061:9025 6021:9026 6061:90266022:9024 6062:9024 6022:9025 6062:9025 6022:9026 6062:9026 6023:90246063:9024 6023:9025 6063:9025 6023:9026 6063:9026 6024:9024 6064:90246024:9025 6064:9025 6024:9026 6064:9026 6025:9024 6065:9024 6025:90256065:9025 6025:9026 6065:9026 6026:9024 6066:9024 6026:9025 6066:90256026:9026 6066:9026 6027:9024 6067:9024 6027:9025 6067:9025 6027:90266067:9026 6028:9024 6068:9024 6028:9025 6068:9025 6028:9026 6068:90266029:9024 6069:9024 6029:9025 6069:9025 6029:9026 6069:9026 6030:90246070:9024 6030:9025 6070:9025 6030:9026 6070:9026 6031:9024 6071:90246031:9025 6071:9025 6031:9026 6071:9026 6032:9024 6072:9024 6032:90256072:9025 6032:9026 6072:9026 6033:9024 6073:9024 6033:9025 6073:90256033:9026 6073:9026 6034:9024 6074:9024 6034:9025 6074:9025 6034:90266074:9026 6035:9024 6075:9024 6035:9025 6075:9025 6035:9026 6075:90266036:9024 6076:9024 6036:9025 6076:9025 6036:9026 6076:9026 6037:90246077:9024 6037:9025 6077:9025 6037:9026 6077:9026 6038:9024 6078:90246038:9025 6078:9025 6038:9026 6078:9026 6039:9024 6039:9025 6039:90266000:9027 6040:9027 6000:9028 6040:9028 6000:9029 6040:9029 6001:90276041:9027 6001:9028 6041:9028 6001:9029 6041:9029 6002:9027 6042:90276002:9028 6042:9028 6002:9029 6042:9029 6003:9027 6043:9027 6003:90286043:9028 6003:9029 6043:9029 6004:9027 6044:9027 6004:9028 6044:90286004:9029 6044:9029 6005:9027 6045:9027 6005:9028 6045:9028 6005:90296045:9029 6006:9027 6046:9027 6006:9028 6046:9028 6006:9029 6046:90296007:9027 6047:9027 6007:9028 6047:9028 6007:9029 6047:9029 6008:90276048:9027 6008:9028 6048:9028 6008:9029 6048:9029 6009:9027 6049:90276009:9028 6049:9028 6009:9029 6049:9029 6010:9027 6050:9027 6010:90286050:9028 6010:9029 6050:9029 6011:9027 6051:9027 6011:9028 6051:90286011:9029 6051:9029 6012:9027 6052:9027 6012:9028 6052:9028 6012:90296052:9029 6013:9027 6053:9027 6013:9028 6053:9028 6013:9029 6053:90296014:9027 6054:9027 6014:9028 6054:9028 6014:9029 6054:9029 6015:90276055:9027 6015:9028 6055:9028 6015:9029 6055:9029 6016:9027 6056:90276016:9028 6056:9028 6016:9029 6056:9029 6017:9027 6057:9027 6017:90286057:9028 6017:9029 6057:9029 6018:9027 6058:9027 6018:9028 6058:90286018:9029 6058:9029 6019:9027 6059:9027 6019:9028 6059:9028 6019:90296059:9029 6020:9027 6060:9027 6020:9028 6060:9028 6020:9029 6060:90296021:9027 6061:9027 6021:9028 6061:9028 6021:9029 6061:9029 6022:90276062:9027 6022:9028 6062:9028 6022:9029 6062:9029 6023:9027 6063:90276023:9028 6063:9028 6023:9029 6063:9029 6024:9027 6064:9027 6024:90286064:9028 6024:9029 6064:9029 6025:9027 6065:9027 6025:9028 6065:90286025:9029 6065:9029 6026:9027 6066:9027 6026:9028 6066:9028 6026:90296066:9029 6027:9027 6067:9027 6027:9028 6067:9028 6027:9029 6067:90296028:9027 6068:9027 6028:9028 6068:9028 6028:9029 6068:9029 6029:90276069:9027 6029:9028 6069:9028 6029:9029 6069:9029 6030:9027 6070:90276030:9028 6070:9028 6030:9029 6070:9029 6031:9027 6071:9027 6031:90286071:9028 6031:9029 6071:9029 6032:9027 6072:9027 6032:9028 6072:90286032:9029 6072:9029 6033:9027 6073:9027 6033:9028 6073:9028 6033:90296073:9029 6034:9027 6074:9027 6034:9028 6074:9028 6034:9029 6074:90296035:9027 6075:9027 6035:9028 6075:9028 6035:9029 6075:9029 6036:90276076:9027 6036:9028 6076:9028 6036:9029 6076:9029 6037:9027 6077:90276037:9028 6077:9028 6037:9029 6077:9029 6038:9027 6078:9027 6038:90286078:9028 6038:9029 6078:9029 6039:9027 6039:9028 6039:9029 6000:90306040:9030 6000:9031 6040:9031 6000:9032 6040:9032 6001:9030 6041:90306001:9031 6041:9031 6001:9032 6041:9032 6002:9030 6042:9030 6002:90316042:9031 6002:9032 6042:9032 6003:9030 6043:9030 6003:9031 6043:90316003:9032 6043:9032 6004:9030 6044:9030 6004:9031 6044:9031 6004:90326044:9032 6005:9030 6045:9030 6005:9031 6045:9031 6005:9032 6045:90326006:9030 6046:9030 6006:9031 6046:9031 6006:9032 6046:9032 6007:90306047:9030 6007:9031 6047:9031 6007:9032 6047:9032 6008:9030 6048:90306008:9031 6048:9031 6008:9032 6048:9032 6009:9030 6049:9030 6009:90316049:9031 6009:9032 6049:9032 6010:9030 6050:9030 6010:9031 6050:90316010:9032 6050:9032 6011:9030 6051:9030 6011:9031 6051:9031 6011:90326051:9032 6012:9030 6052:9030 6012:9031 6052:9031 6012:9032 6052:90326013:9030 6053:9030 6013:9031 6053:9031 6013:9032 6053:9032 6014:90306054:9030 6014:9031 6054:9031 6014:9032 6054:9032 6015:9030 6055:90306015:9031 6055:9031 6015:9032 6055:9032 6016:9030 6056:9030 6016:90316056:9031 6016:9032 6056:9032 6017:9030 6057:9030 6017:9031 6057:90316017:9032 6057:9032 6018:9030 6058:9030 6018:9031 6058:9031 6018:90326058:9032 6019:9030 6059:9030 6019:9031 6059:9031 6019:9032 6059:90326020:9030 6060:9030 6020:9031 6060:9031 6020:9032 6060:9032 6021:90306061:9030 6021:9031 6061:9031 6021:9032 6061:9032 6022:9030 6062:90306022:9031 6062:9031 6022:9032 6062:9032 6023:9030 6063:9030 6023:90316063:9031 6023:9032 6063:9032 6024:9030 6064:9030 6024:9031 6064:90316024:9032 6064:9032 6025:9030 6065:9030 6025:9031 6065:9031 6025:90326065:9032 6026:9030 6066:9030 6026:9031 6066:9031 6026:9032 6066:90326027:9030 6067:9030 6027:9031 6067:9031 6027:9032 6067:9032 6028:90306068:9030 6028:9031 6068:9031 6028:9032 6068:9032 6029:9030 6069:90306029:9031 6069:9031 6029:9032 6069:9032 6030:9030 6070:9030 6030:90316070:9031 6030:9032 6070:9032 6031:9030 6071:9030 6031:9031 6071:90316031:9032 6071:9032 6032:9030 6072:9030 6032:9031 6072:9031 6032:90326072:9032 6033:9030 6073:9030 6033:9031 6073:9031 6033:9032 6073:90326034:9030 6074:9030 6034:9031 6074:9031 6034:9032 6074:9032 6035:90306075:9030 6035:9031 6075:9031 6035:9032 6075:9032 6036:9030 6076:90306036:9031 6076:9031 6036:9032 6076:9032 6037:9030 6077:9030 6037:90316077:9031 6037:9032 6077:9032 6038:9030 6078:9030 6038:9031 6078:90316038:9032 6078:9032 6039:9030 6039:9031 6039:9032 6000:9033 6040:90336000:9034 6040:9034 6000:9035 6040:9035 6001:9033 6041:9033 6001:90346041:9034 6001:9035 6041:9035 6002:9033 6042:9033 6002:9034 6042:90346002:9035 6042:9035 6003:9033 6043:9033 6003:9034 6043:9034 6003:90356043:9035 6004:9033 6044:9033 6004:9034 6044:9034 6004:9035 6044:90356005:9033 6045:9033 6005:9034 6045:9034 6005:9035 6045:9035 6006:90336046:9033 6006:9034 6046:9034 6006:9035 6046:9035 6007:9033 6047:90336007:9034 6047:9034 6007:9035 6047:9035 6008:9033 6048:9033 6008:90346048:9034 6008:9035 6048:9035 6009:9033 6049:9033 6009:9034 6049:90346009:9035 6049:9035 6010:9033 6050:9033 6010:9034 6050:9034 6010:90356050:9035 6011:9033 6051:9033 6011:9034 6051:9034 6011:9035 6051:90356012:9033 6052:9033 6012:9034 6052:9034 6012:9035 6052:9035 6013:90336053:9033 6013:9034 6053:9034 6013:9035 6053:9035 6014:9033 6054:90336014:9034 6054:9034 6014:9035 6054:9035 6015:9033 6055:9033 6015:90346055:9034 6015:9035 6055:9035 6016:9033 6056:9033 6016:9034 6056:90346016:9035 6056:9035 6017:9033 6057:9033 6017:9034 6057:9034 6017:90356057:9035 6018:9033 6058:9033 6018:9034 6058:9034 6018:9035 6058:90356019:9033 6059:9033 6019:9034 6059:9034 6019:9035 6059:9035 6020:90336060:9033 6020:9034 6060:9034 6020:9035 6060:9035 6021:9033 6061:90336021:9034 6061:9034 6021:9035 6061:9035 6022:9033 6062:9033 6022:90346062:9034 6022:9035 6062:9035 6023:9033 6063:9033 6023:9034 6063:90346023:9035 6063:9035 6024:9033 6064:9033 6024:9034 6064:9034 6024:90356064:9035 6025:9033 6065:9033 6025:9034 6065:9034 6025:9035 6065:90356026:9033 6066:9033 6026:9034 6066:9034 6026:9035 6066:9035 6027:90336067:9033 6027:9034 6067:9034 6027:9035 6067:9035 6028:9033 6068:90336028:9034 6068:9034 6028:9035 6068:9035 6029:9033 6069:9033 6029:90346069:9034 6029:9035 6069:9035 6030:9033 6070:9033 6030:9034 6070:90346030:9035 6070:9035 6031:9033 6071:9033 6031:9034 6071:9034 6031:90356071:9035 6032:9033 6072:9033 6032:9034 6072:9034 6032:9035 6072:90356033:9033 6073:9033 6033:9034 6073:9034 6033:9035 6073:9035 6034:90336074:9033 6034:9034 6074:9034 6034:9035 6074:9035 6035:9033 6075:90336035:9034 6075:9034 6035:9035 6075:9035 6036:9033 6076:9033 6036:90346076:9034 6036:9035 6076:9035 6037:9033 6077:9033 6037:9034 6077:90346037:9035 6077:9035 6038:9033 6078:9033 6038:9034 6078:9034 6038:90356078:9035 6039:9033 6039:9034 6039:9035 6000:9036 6040:9036 6000:90376040:9037 6000:9038 6040:9038 6001:9036 6041:9036 6001:9037 6041:90376001:9038 6041:9038 6002:9036 6042:9036 6002:9037 6042:9037 6002:90386042:9038 6003:9036 6043:9036 6003:9037 6043:9037 6003:9038 6043:90386004:9036 6044:9036 6004:9037 6044:9037 6004:9038 6044:9038 6005:90366045:9036 6005:9037 6045:9037 6005:9038 6045:9038 6006:9036 6046:90366006:9037 6046:9037 6006:9038 6046:9038 6007:9036 6047:9036 6007:90376047:9037 6007:9038 6047:9038 6008:9036 6048:9036 6008:9037 6048:90376008:9038 6048:9038 6009:9036 6049:9036 6009:9037 6049:9037 6009:90386049:9038 6010:9036 6050:9036 6010:9037 6050:9037 6010:9038 6050:90386011:9036 6051:9036 6011:9037 6051:9037 6011:9038 6051:9038 6012:90366052:9036 6012:9037 6052:9037 6012:9038 6052:9038 6013:9036 6053:90366013:9037 6053:9037 6013:9038 6053:9038 6014:9036 6054:9036 6014:90376054:9037 6014:9038 6054:9038 6015:9036 6055:9036 6015:9037 6055:90376015:9038 6055:9038 6016:9036 6056:9036 6016:9037 6056:9037 6016:90386056:9038 6017:9036 6057:9036 6017:9037 6057:9037 6017:9038 6057:90386018:9036 6058:9036 6018:9037 6058:9037 6018:9038 6058:9038 6019:90366059:9036 6019:9037 6059:9037 6019:9038 6059:9038 6020:9036 6060:90366020:9037 6060:9037 6020:9038 6060:9038 6021:9036 6061:9036 6021:90376061:9037 6021:9038 6061:9038 6022:9036 6062:9036 6022:9037 6062:90376022:9038 6062:9038 6023:9036 6063:9036 6023:9037 6063:9037 6023:90386063:9038 6024:9036 6064:9036 6024:9037 6064:9037 6024:9038 6064:90386025:9036 6065:9036 6025:9037 6065:9037 6025:9038 6065:9038 6026:90366066:9036 6026:9037 6066:9037 6026:9038 6066:9038 6027:9036 6067:90366027:9037 6067:9037 6027:9038 6067:9038 6028:9036 6068:9036 6028:90376068:9037 6028:9038 6068:9038 6029:9036 6069:9036 6029:9037 6069:90376029:9038 6069:9038 6030:9036 6070:9036 6030:9037 6070:9037 6030:90386070:9038 6031:9036 6071:9036 6031:9037 6071:9037 6031:9038 6071:90386032:9036 6072:9036 6032:9037 6072:9037 6032:9038 6072:9038 6033:90366073:9036 6033:9037 6073:9037 6033:9038 6073:9038 6034:9036 6074:90366034:9037 6074:9037 6034:9038 6074:9038 6035:9036 6075:9036 6035:90376075:9037 6035:9038 6075:9038 6036:9036 6076:9036 6036:9037 6076:90376036:9038 6076:9038 6037:9036 6077:9036 6037:9037 6077:9037 6037:90386077:9038 6038:9036 6078:9036 6038:9037 6078:9037 6038:9038 6078:90386039:9036 6039:9037 6039:9038 6000:9039 6040:9039 6000:9040 6040:90406000:9041 6040:9041 6001:9039 6041:9039 6001:9040 6041:9040 6001:90416041:9041 6002:9039 6042:9039 6002:9040 6042:9040 6002:9041 6042:90416003:9039 6043:9039 6003:9040 6043:9040 6003:9041 6043:9041 6004:90396044:9039 6004:9040 6044:9040 6004:9041 6044:9041 6005:9039 6045:90396005:9040 6045:9040 6005:9041 6045:9041 6006:9039 6046:9039 6006:90406046:9040 6006:9041 6046:9041 6007:9039 6047:9039 6007:9040 6047:90406007:9041 6047:9041 6008:9039 6048:9039 6008:9040 6048:9040 6008:90416048:9041 6009:9039 6049:9039 6009:9040 6049:9040 6009:9041 6049:90416010:9039 6050:9039 6010:9040 6050:9040 6010:9041 6050:9041 6011:90396051:9039 6011:9040 6051:9040 6011:9041 6051:9041 6012:9039 6052:90396012:9040 6052:9040 6012:9041 6052:9041 6013:9039 6053:9039 6013:90406053:9040 6013:9041 6053:9041 6014:9039 6054:9039 6014:9040 6054:90406014:9041 6054:9041 6015:9039 6055:9039 6015:9040 6055:9040 6015:90416055:9041 6016:9039 6056:9039 6016:9040 6056:9040 6016:9041 6056:90416017:9039 6057:9039 6017:9040 6057:9040 6017:9041 6057:9041 6018:90396058:9039 6018:9040 6058:9040 6018:9041 6058:9041 6019:9039 6059:90396019:9040 6059:9040 6019:9041 6059:9041 6020:9039 6060:9039 6020:90406060:9040 6020:9041 6060:9041 6021:9039 6061:9039 6021:9040 6061:90406021:9041 6061:9041 6022:9039 6062:9039 6022:9040 6062:9040 6022:90416062:9041 6023:9039 6063:9039 6023:9040 6063:9040 6023:9041 6063:90416024:9039 6064:9039 6024:9040 6064:9040 6024:9041 6064:9041 6025:90396065:9039 6025:9040 6065:9040 6025:9041 6065:9041 6026:9039 6066:90396026:9040 6066:9040 6026:9041 6066:9041 6027:9039 6067:9039 6027:90406067:9040 6027:9041 6067:9041 6028:9039 6068:9039 6028:9040 6068:90406028:9041 6068:9041 6029:9039 6069:9039 6029:9040 6069:9040 6029:90416069:9041 6030:9039 6070:9039 6030:9040 6070:9040 6030:9041 6070:90416031:9039 6071:9039 6031:9040 6071:9040 6031:9041 6071:9041 6032:90396072:9039 6032:9040 6072:9040 6032:9041 6072:9041 6033:9039 6073:90396033:9040 6073:9040 6033:9041 6073:9041 6034:9039 6074:9039 6034:90406074:9040 6034:9041 6074:9041 6035:9039 6075:9039 6035:9040 6075:90406035:9041 6075:9041 6036:9039 6076:9039 6036:9040 6076:9040 6036:90416076:9041 6037:9039 6077:9039 6037:9040 6077:9040 6037:9041 6077:90416038:9039 6078:9039 6038:9040 6078:9040 6038:9041 6078:9041 6039:90396039:9040 6039:9041 6000:9042 6040:9042 6000:9043 6040:9043 6000:90446040:9044 6001:9042 6041:9042 6001:9043 6041:9043 6001:9044 6041:90446002:9042 6042:9042 6002:9043 6042:9043 6002:9044 6042:9044 6003:90426043:9042 6003:9043 6043:9043 6003:9044 6043:9044 6004:9042 6044:90426004:9043 6044:9043 6004:9044 6044:9044 6005:9042 6045:9042 6005:90436045:9043 6005:9044 6045:9044 6006:9042 6046:9042 6006:9043 6046:90436006:9044 6046:9044 6007:9042 6047:9042 6007:9043 6047:9043 6007:90446047:9044 6008:9042 6048:9042 6008:9043 6048:9043 6008:9044 6048:90446009:9042 6049:9042 6009:9043 6049:9043 6009:9044 6049:9044 6010:90426050:9042 6010:9043 6050:9043 6010:9044 6050:9044 6011:9042 6051:90426011:9043 6051:9043 6011:9044 6051:9044 6012:9042 6052:9042 6012:90436052:9043 6012:9044 6052:9044 6013:9042 6053:9042 6013:9043 6053:90436013:9044 6053:9044 6014:9042 6054:9042 6014:9043 6054:9043 6014:90446054:9044 6015:9042 6055:9042 6015:9043 6055:9043 6015:9044 6055:90446016:9042 6056:9042 6016:9043 6056:9043 6016:9044 6056:9044 6017:90426057:9042 6017:9043 6057:9043 6017:9044 6057:9044 6018:9042 6058:90426018:9043 6058:9043 6018:9044 6058:9044 6019:9042 6059:9042 6019:90436059:9043 6019:9044 6059:9044 6020:9042 6060:9042 6020:9043 6060:90436020:9044 6060:9044 6021:9042 6061:9042 6021:9043 6061:9043 6021:90446061:9044 6022:9042 6062:9042 6022:9043 6062:9043 6022:9044 6062:90446023:9042 6063:9042 6023:9043 6063:9043 6023:9044 6063:9044 6024:90426064:9042 6024:9043 6064:9043 6024:9044 6064:9044 6025:9042 6065:90426025:9043 6065:9043 6025:9044 6065:9044 6026:9042 6066:9042 6026:90436066:9043 6026:9044 6066:9044 6027:9042 6067:9042 6027:9043 6067:90436027:9044 6067:9044 6028:9042 6068:9042 6028:9043 6068:9043 6028:90446068:9044 6029:9042 6069:9042 6029:9043 6069:9043 6029:9044 6069:90446030:9042 6070:9042 6030:9043 6070:9043 6030:9044 6070:9044 6031:90426071:9042 6031:9043 6071:9043 6031:9044 6071:9044 6032:9042 6072:90426032:9043 6072:9043 6032:9044 6072:9044 6033:9042 6073:9042 6033:90436073:9043 6033:9044 6073:9044 6034:9042 6074:9042 6034:9043 6074:90436034:9044 6074:9044 6035:9042 6075:9042 6035:9043 6075:9043 6035:90446075:9044 6036:9042 6076:9042 6036:9043 6076:9043 6036:9044 6076:90446037:9042 6077:9042 6037:9043 6077:9043 6037:9044 6077:9044 6038:90426078:9042 6038:9043 6078:9043 6038:9044 6078:9044 6039:9042 6039:90436039:9044 6000:9045 6040:9045 6000:9046 6040:9046 6000:9047 6040:90476001:9045 6041:9045 6001:9046 6041:9046 6001:9047 6041:9047 6002:90456042:9045 6002:9046 6042:9046 6002:9047 6042:9047 6003:9045 6043:90456003:9046 6043:9046 6003:9047 6043:9047 6004:9045 6044:9045 6004:90466044:9046 6004:9047 6044:9047 6005:9045 6045:9045 6005:9046 6045:90466005:9047 6045:9047 6006:9045 6046:9045 6006:9046 6046:9046 6006:90476046:9047 6007:9045 6047:9045 6007:9046 6047:9046 6007:9047 6047:90476008:9045 6048:9045 6008:9046 6048:9046 6008:9047 6048:9047 6009:90456049:9045 6009:9046 6049:9046 6009:9047 6049:9047 6010:9045 6050:90456010:9046 6050:9046 6010:9047 6050:9047 6011:9045 6051:9045 6011:90466051:9046 6011:9047 6051:9047 6012:9045 6052:9045 6012:9046 6052:90466012:9047 6052:9047 6013:9045 6053:9045 6013:9046 6053:9046 6013:90476053:9047 6014:9045 6054:9045 6014:9046 6054:9046 6014:9047 6054:90476015:9045 6055:9045 6015:9046 6055:9046 6015:9047 6055:9047 6016:90456056:9045 6016:9046 6056:9046 6016:9047 6056:9047 6017:9045 6057:90456017:9046 6057:9046 6017:9047 6057:9047 6018:9045 6058:9045 6018:90466058:9046 6018:9047 6058:9047 6019:9045 6059:9045 6019:9046 6059:90466019:9047 6059:9047 6020:9045 6060:9045 6020:9046 6060:9046 6020:90476060:9047 6021:9045 6061:9045 6021:9046 6061:9046 6021:9047 6061:90476022:9045 6062:9045 6022:9046 6062:9046 6022:9047 6062:9047 6023:90456063:9045 6023:9046 6063:9046 6023:9047 6063:9047 6024:9045 6064:90456024:9046 6064:9046 6024:9047 6064:9047 6025:9045 6065:9045 6025:90466065:9046 6025:9047 6065:9047 6026:9045 6066:9045 6026:9046 6066:90466026:9047 6066:9047 6027:9045 6067:9045 6027:9046 6067:9046 6027:90476067:9047 6028:9045 6068:9045 6028:9046 6068:9046 6028:9047 6068:90476029:9045 6069:9045 6029:9046 6069:9046 6029:9047 6069:9047 6030:90456070:9045 6030:9046 6070:9046 6030:9047 6070:9047 6031:9045 6071:90456031:9046 6071:9046 6031:9047 6071:9047 6032:9045 6072:9045 6032:90466072:9046 6032:9047 6072:9047 6033:9045 6073:9045 6033:9046 6073:90466033:9047 6073:9047 6034:9045 6074:9045 6034:9046 6074:9046 6034:90476074:9047 6035:9045 6075:9045 6035:9046 6075:9046 6035:9047 6075:90476036:9045 6076:9045 6036:9046 6076:9046 6036:9047 6076:9047 6037:90456077:9045 6037:9046 6077:9046 6037:9047 6077:9047 6038:9045 6078:90456038:9046 6078:9046 6038:9047 6078:9047 6039:9045 6039:9046 6039:90476000:9048 6040:9048 6000:9049 6040:9049 6000:9050 6040:9050 6001:90486041:9048 6001:9049 6041:9049 6001:9050 6041:9050 6002:9048 6042:90486002:9049 6042:9049 6002:9050 6042:9050 6003:9048 6043:9048 6003:90496043:9049 6003:9050 6043:9050 6004:9048 6044:9048 6004:9049 6044:90496004:9050 6044:9050 6005:9048 6045:9048 6005:9049 6045:9049 6005:90506045:9050 6006:9048 6046:9048 6006:9049 6046:9049 6006:9050 6046:90506007:9048 6047:9048 6007:9049 6047:9049 6007:9050 6047:9050 6008:90486048:9048 6008:9049 6048:9049 6008:9050 6048:9050 6009:9048 6049:90486009:9049 6049:9049 6009:9050 6049:9050 6010:9048 6050:9048 6010:90496050:9049 6010:9050 6050:9050 6011:9048 6051:9048 6011:9049 6051:90496011:9050 6051:9050 6012:9048 6052:9048 6012:9049 6052:9049 6012:90506052:9050 6013:9048 6053:9048 6013:9049 6053:9049 6013:9050 6053:90506014:9048 6054:9048 6014:9049 6054:9049 6014:9050 6054:9050 6015:90486055:9048 6015:9049 6055:9049 6015:9050 6055:9050 6016:9048 6056:90486016:9049 6056:9049 6016:9050 6056:9050 6017:9048 6057:9048 6017:90496057:9049 6017:9050 6057:9050 6018:9048 6058:9048 6018:9049 6058:90496018:9050 6058:9050 6019:9048 6059:9048 6019:9049 6059:9049 6019:90506059:9050 6020:9048 6060:9048 6020:9049 6060:9049 6020:9050 6060:90506021:9048 6061:9048 6021:9049 6061:9049 6021:9050 6061:9050 6022:90486062:9048 6022:9049 6062:9049 6022:9050 6062:9050 6023:9048 6063:90486023:9049 6063:9049 6023:9050 6063:9050 6024:9048 6064:9048 6024:90496064:9049 6024:9050 6064:9050 6025:9048 6065:9048 6025:9049 6065:90496025:9050 6065:9050 6026:9048 6066:9048 6026:9049 6066:9049 6026:90506066:9050 6027:9048 6067:9048 6027:9049 6067:9049 6027:9050 6067:90506028:9048 6068:9048 6028:9049 6068:9049 6028:9050 6068:9050 6029:90486069:9048 6029:9049 6069:9049 6029:9050 6069:9050 6030:9048 6070:90486030:9049 6070:9049 6030:9050 6070:9050 6031:9048 6071:9048 6031:90496071:9049 6031:9050 6071:9050 6032:9048 6072:9048 6032:9049 6072:90496032:9050 6072:9050 6033:9048 6073:9048 6033:9049 6073:9049 6033:90506073:9050 6034:9048 6074:9048 6034:9049 6074:9049 6034:9050 6074:90506035:9048 6075:9048 6035:9049 6075:9049 6035:9050 6075:9050 6036:90486076:9048 6036:9049 6076:9049 6036:9050 6076:9050 6037:9048 6077:90486037:9049 6077:9049 6037:9050 6077:9050 6038:9048 6078:9048 6038:90496078:9049 6038:9050 6078:9050 6039:9048 6039:9049 6039:9050 6000:90516040:9051 6000:9052 6040:9052 6000:9053 6040:9053 6001:9051 6041:90516001:9052 6041:9052 6001:9053 6041:9053 6002:9051 6042:9051 6002:90526042:9052 6002:9053 6042:9053 6003:9051 6043:9051 6003:9052 6043:90526003:9053 6043:9053 6004:9051 6044:9051 6004:9052 6044:9052 6004:90536044:9053 6005:9051 6045:9051 6005:9052 6045:9052 6005:9053 6045:90536006:9051 6046:9051 6006:9052 6046:9052 6006:9053 6046:9053 6007:90516047:9051 6007:9052 6047:9052 6007:9053 6047:9053 6008:9051 6048:90516008:9052 6048:9052 6008:9053 6048:9053 6009:9051 6049:9051 6009:90526049:9052 6009:9053 6049:9053 6010:9051 6050:9051 6010:9052 6050:90526010:9053 6050:9053 6011:9051 6051:9051 6011:9052 6051:9052 6011:90536051:9053 6012:9051 6052:9051 6012:9052 6052:9052 6012:9053 6052:90536013:9051 6053:9051 6013:9052 6053:9052 6013:9053 6053:9053 6014:90516054:9051 6014:9052 6054:9052 6014:9053 6054:9053 6015:9051 6055:90516015:9052 6055:9052 6015:9053 6055:9053 6016:9051 6056:9051 6016:90526056:9052 6016:9053 6056:9053 6017:9051 6057:9051 6017:9052 6057:90526017:9053 6057:9053 6018:9051 6058:9051 6018:9052 6058:9052 6018:90536058:9053 6019:9051 6059:9051 6019:9052 6059:9052 6019:9053 6059:90536020:9051 6060:9051 6020:9052 6060:9052 6020:9053 6060:9053 6021:90516061:9051 6021:9052 6061:9052 6021:9053 6061:9053 6022:9051 6062:90516022:9052 6062:9052 6022:9053 6062:9053 6023:9051 6063:9051 6023:90526063:9052 6023:9053 6063:9053 6024:9051 6064:9051 6024:9052 6064:90526024:9053 6064:9053 6025:9051 6065:9051 6025:9052 6065:9052 6025:90536065:9053 6026:9051 6066:9051 6026:9052 6066:9052 6026:9053 6066:90536027:9051 6067:9051 6027:9052 6067:9052 6027:9053 6067:9053 6028:90516068:9051 6028:9052 6068:9052 6028:9053 6068:9053 6029:9051 6069:90516029:9052 6069:9052 6029:9053 6069:9053 6030:9051 6070:9051 6030:90526070:9052 6030:9053 6070:9053 6031:9051 6071:9051 6031:9052 6071:90526031:9053 6071:9053 6032:9051 6072:9051 6032:9052 6072:9052 6032:90536072:9053 6033:9051 6073:9051 6033:9052 6073:9052 6033:9053 6073:90536034:9051 6074:9051 6034:9052 6074:9052 6034:9053 6074:9053 6035:90516075:9051 6035:9052 6075:9052 6035:9053 6075:9053 6036:9051 6076:90516036:9052 6076:9052 6036:9053 6076:9053 6037:9051 6077:9051 6037:90526077:9052 6037:9053 6077:9053 6038:9051 6078:9051 6038:9052 6078:90526038:9053 6078:9053 6039:9051 6039:9052 6039:9053 6000:9054 6040:90546000:9055 6040:9055 6000:9056 6040:9056 6001:9054 6041:9054 6001:90556041:9055 6001:9056 6041:9056 6002:9054 6042:9054 6002:9055 6042:90556002:9056 6042:9056 6003:9054 6043:9054 6003:9055 6043:9055 6003:90566043:9056 6004:9054 6044:9054 6004:9055 6044:9055 6004:9056 6044:90566005:9054 6045:9054 6005:9055 6045:9055 6005:9056 6045:9056 6006:90546046:9054 6006:9055 6046:9055 6006:9056 6046:9056 6007:9054 6047:90546007:9055 6047:9055 6007:9056 6047:9056 6008:9054 6048:9054 6008:90556048:9055 6008:9056 6048:9056 6009:9054 6049:9054 6009:9055 6049:90556009:9056 6049:9056 6010:9054 6050:9054 6010:9055 6050:9055 6010:90566050:9056 6011:9054 6051:9054 6011:9055 6051:9055 6011:9056 6051:90566012:9054 6052:9054 6012:9055 6052:9055 6012:9056 6052:9056 6013:90546053:9054 6013:9055 6053:9055 6013:9056 6053:9056 6014:9054 6054:90546014:9055 6054:9055 6014:9056 6054:9056 6015:9054 6055:9054 6015:90556055:9055 6015:9056 6055:9056 6016:9054 6056:9054 6016:9055 6056:90556016:9056 6056:9056 6017:9054 6057:9054 6017:9055 6057:9055 6017:90566057:9056 6018:9054 6058:9054 6018:9055 6058:9055 6018:9056 6058:90566019:9054 6059:9054 6019:9055 6059:9055 6019:9056 6059:9056 6020:90546060:9054 6020:9055 6060:9055 6020:9056 6060:9056 6021:9054 6061:90546021:9055 6061:9055 6021:9056 6061:9056 6022:9054 6062:9054 6022:90556062:9055 6022:9056 6062:9056 6023:9054 6063:9054 6023:9055 6063:90556023:9056 6063:9056 6024:9054 6064:9054 6024:9055 6064:9055 6024:90566064:9056 6025:9054 6065:9054 6025:9055 6065:9055 6025:9056 6065:90566026:9054 6066:9054 6026:9055 6066:9055 6026:9056 6066:9056 6027:90546067:9054 6027:9055 6067:9055 6027:9056 6067:9056 6028:9054 6068:90546028:9055 6068:9055 6028:9056 6068:9056 6029:9054 6069:9054 6029:90556069:9055 6029:9056 6069:9056 6030:9054 6070:9054 6030:9055 6070:90556030:9056 6070:9056 6031:9054 6071:9054 6031:9055 6071:9055 6031:90566071:9056 6032:9054 6072:9054 6032:9055 6072:9055 6032:9056 6072:90566033:9054 6073:9054 6033:9055 6073:9055 6033:9056 6073:9056 6034:90546074:9054 6034:9055 6074:9055 6034:9056 6074:9056 6035:9054 6075:90546035:9055 6075:9055 6035:9056 6075:9056 6036:9054 6076:9054 6036:90556076:9055 6036:9056 6076:9056 6037:9054 6077:9054 6037:9055 6077:90556037:9056 6077:9056 6038:9054 6078:9054 6038:9055 6078:9055 6038:90566078:9056 6039:9054 6039:9055 6039:9056 6000:9057 6040:9057 6000:90586040:9058 6000:9059 6040:9059 6001:9057 6041:9057 6001:9058 6041:90586001:9059 6041:9059 6002:9057 6042:9057 6002:9058 6042:9058 6002:90596042:9059 6003:9057 6043:9057 6003:9058 6043:9058 6003:9059 6043:90596004:9057 6044:9057 6004:9058 6044:9058 6004:9059 6044:9059 6005:90576045:9057 6005:9058 6045:9058 6005:9059 6045:9059 6006:9057 6046:90576006:9058 6046:9058 6006:9059 6046:9059 6007:9057 6047:9057 6007:90586047:9058 6007:9059 6047:9059 6008:9057 6048:9057 6008:9058 6048:90586008:9059 6048:9059 6009:9057 6049:9057 6009:9058 6049:9058 6009:90596049:9059 6010:9057 6050:9057 6010:9058 6050:9058 6010:9059 6050:90596011:9057 6051:9057 6011:9058 6051:9058 6011:9059 6051:9059 6012:90576052:9057 6012:9058 6052:9058 6012:9059 6052:9059 6013:9057 6053:90576013:9058 6053:9058 6013:9059 6053:9059 6014:9057 6054:9057 6014:90586054:9058 6014:9059 6054:9059 6015:9057 6055:9057 6015:9058 6055:90586015:9059 6055:9059 6016:9057 6056:9057 6016:9058 6056:9058 6016:90596056:9059 6017:9057 6057:9057 6017:9058 6057:9058 6017:9059 6057:90596018:9057 6058:9057 6018:9058 6058:9058 6018:9059 6058:9059 6019:90576059:9057 6019:9058 6059:9058 6019:9059 6059:9059 6020:9057 6060:90576020:9058 6060:9058 6020:9059 6060:9059 6021:9057 6061:9057 6021:90586061:9058 6021:9059 6061:9059 6022:9057 6062:9057 6022:9058 6062:90586022:9059 6062:9059 6023:9057 6063:9057 6023:9058 6063:9058 6023:90596063:9059 6024:9057 6064:9057 6024:9058 6064:9058 6024:9059 6064:90596025:9057 6065:9057 6025:9058 6065:9058 6025:9059 6065:9059 6026:90576066:9057 6026:9058 6066:9058 6026:9059 6066:9059 6027:9057 6067:90576027:9058 6067:9058 6027:9059 6067:9059 6028:9057 6068:9057 6028:90586068:9058 6028:9059 6068:9059 6029:9057 6069:9057 6029:9058 6069:90586029:9059 6069:9059 6030:9057 6070:9057 6030:9058 6070:9058 6030:90596070:9059 6031:9057 6071:9057 6031:9058 6071:9058 6031:9059 6071:90596032:9057 6072:9057 6032:9058 6072:9058 6032:9059 6072:9059 6033:90576073:9057 6033:9058 6073:9058 6033:9059 6073:9059 6034:9057 6074:90576034:9058 6074:9058 6034:9059 6074:9059 6035:9057 6075:9057 6035:90586075:9058 6035:9059 6075:9059 6036:9057 6076:9057 6036:9058 6076:90586036:9059 6076:9059 6037:9057 6077:9057 6037:9058 6077:9058 6037:90596077:9059 6038:9057 6078:9057 6038:9058 6078:9058 6038:9059 6078:90596039:9057 6039:9058 6039:9059 6000:9060 6040:9060 6000:9061 6040:90616000:9062 6040:9062 6001:9060 6041:9060 6001:9061 6041:9061 6001:90626041:9062 6002:9060 6042:9060 6002:9061 6042:9061 6002:9062 6042:90626003:9060 6043:9060 6003:9061 6043:9061 6003:9062 6043:9062 6004:90606044:9060 6004:9061 6044:9061 6004:9062 6044:9062 6005:9060 6045:90606005:9061 6045:9061 6005:9062 6045:9062 6006:9060 6046:9060 6006:90616046:9061 6006:9062 6046:9062 6007:9060 6047:9060 6007:9061 6047:90616007:9062 6047:9062 6008:9060 6048:9060 6008:9061 6048:9061 6008:90626048:9062 6009:9060 6049:9060 6009:9061 6049:9061 6009:9062 6049:90626010:9060 6050:9060 6010:9061 6050:9061 6010:9062 6050:9062 6011:90606051:9060 6011:9061 6051:9061 6011:9062 6051:9062 6012:9060 6052:90606012:9061 6052:9061 6012:9062 6052:9062 6013:9060 6053:9060 6013:90616053:9061 6013:9062 6053:9062 6014:9060 6054:9060 6014:9061 6054:90616014:9062 6054:9062 6015:9060 6055:9060 6015:9061 6055:9061 6015:90626055:9062 6016:9060 6056:9060 6016:9061 6056:9061 6016:9062 6056:90626017:9060 6057:9060 6017:9061 6057:9061 6017:9062 6057:9062 6018:90606058:9060 6018:9061 6058:9061 6018:9062 6058:9062 6019:9060 6059:90606019:9061 6059:9061 6019:9062 6059:9062 6020:9060 6060:9060 6020:90616060:9061 6020:9062 6060:9062 6021:9060 6061:9060 6021:9061 6061:90616021:9062 6061:9062 6022:9060 6062:9060 6022:9061 6062:9061 6022:90626062:9062 6023:9060 6063:9060 6023:9061 6063:9061 6023:9062 6063:90626024:9060 6064:9060 6024:9061 6064:9061 6024:9062 6064:9062 6025:90606065:9060 6025:9061 6065:9061 6025:9062 6065:9062 6026:9060 6066:90606026:9061 6066:9061 6026:9062 6066:9062 6027:9060 6067:9060 6027:90616067:9061 6027:9062 6067:9062 6028:9060 6068:9060 6028:9061 6068:90616028:9062 6068:9062 6029:9060 6069:9060 6029:9061 6069:9061 6029:90626069:9062 6030:9060 6070:9060 6030:9061 6070:9061 6030:9062 6070:90626031:9060 6071:9060 6031:9061 6071:9061 6031:9062 6071:9062 6032:90606072:9060 6032:9061 6072:9061 6032:9062 6072:9062 6033:9060 6073:90606033:9061 6073:9061 6033:9062 6073:9062 6034:9060 6074:9060 6034:90616074:9061 6034:9062 6074:9062 6035:9060 6075:9060 6035:9061 6075:90616035:9062 6075:9062 6036:9060 6076:9060 6036:9061 6076:9061 6036:90626076:9062 6037:9060 6077:9060 6037:9061 6077:9061 6037:9062 6077:90626038:9060 6078:9060 6038:9061 6078:9061 6038:9062 6078:9062 6039:90606039:9061 6039:9062 6000:9063 6040:9063 6000:9064 6040:9064 6000:90656040:9065 6001:9063 6041:9063 6001:9064 6041:9064 6001:9065 6041:90656002:9063 6042:9063 6002:9064 6042:9064 6002:9065 6042:9065 6003:90636043:9063 6003:9064 6043:9064 6003:9065 6043:9065 6004:9063 6044:90636004:9064 6044:9064 6004:9065 6044:9065 6005:9063 6045:9063 6005:90646045:9064 6005:9065 6045:9065 6006:9063 6046:9063 6006:9064 6046:90646006:9065 6046:9065 6007:9063 6047:9063 6007:9064 6047:9064 6007:90656047:9065 6008:9063 6048:9063 6008:9064 6048:9064 6008:9065 6048:90656009:9063 6049:9063 6009:9064 6049:9064 6009:9065 6049:9065 6010:90636050:9063 6010:9064 6050:9064 6010:9065 6050:9065 6011:9063 6051:90636011:9064 6051:9064 6011:9065 6051:9065 6012:9063 6052:9063 6012:90646052:9064 6012:9065 6052:9065 6013:9063 6053:9063 6013:9064 6053:90646013:9065 6053:9065 6014:9063 6054:9063 6014:9064 6054:9064 6014:90656054:9065 6015:9063 6055:9063 6015:9064 6055:9064 6015:9065 6055:90656016:9063 6056:9063 6016:9064 6056:9064 6016:9065 6056:9065 6017:90636057:9063 6017:9064 6057:9064 6017:9065 6057:9065 6018:9063 6058:90636018:9064 6058:9064 6018:9065 6058:9065 6019:9063 6059:9063 6019:90646059:9064 6019:9065 6059:9065 6020:9063 6060:9063 6020:9064 6060:90646020:9065 6060:9065 6021:9063 6061:9063 6021:9064 6061:9064 6021:90656061:9065 6022:9063 6062:9063 6022:9064 6062:9064 6022:9065 6062:90656023:9063 6063:9063 6023:9064 6063:9064 6023:9065 6063:9065 6024:90636064:9063 6024:9064 6064:9064 6024:9065 6064:9065 6025:9063 6065:90636025:9064 6065:9064 6025:9065 6065:9065 6026:9063 6066:9063 6026:90646066:9064 6026:9065 6066:9065 6027:9063 6067:9063 6027:9064 6067:90646027:9065 6067:9065 6028:9063 6068:9063 6028:9064 6068:9064 6028:90656068:9065 6029:9063 6069:9063 6029:9064 6069:9064 6029:9065 6069:90656030:9063 6070:9063 6030:9064 6070:9064 6030:9065 6070:9065 6031:90636071:9063 6031:9064 6071:9064 6031:9065 6071:9065 6032:9063 6072:90636032:9064 6072:9064 6032:9065 6072:9065 6033:9063 6073:9063 6033:90646073:9064 6033:9065 6073:9065 6034:9063 6074:9063 6034:9064 6074:90646034:9065 6074:9065 6035:9063 6075:9063 6035:9064 6075:9064 6035:90656075:9065 6036:9063 6076:9063 6036:9064 6076:9064 6036:9065 6076:90656037:9063 6077:9063 6037:9064 6077:9064 6037:9065 6077:9065 6038:90636078:9063 6038:9064 6078:9064 6038:9065 6078:9065 6039:9063 6039:90646039:9065 6000:9066 6040:9066 6000:9067 6040:9067 6000:9068 6040:90686001:9066 6041:9066 6001:9067 6041:9067 6001:9068 6041:9068 6002:90666042:9066 6002:9067 6042:9067 6002:9068 6042:9068 6003:9066 6043:90666003:9067 6043:9067 6003:9068 6043:9068 6004:9066 6044:9066 6004:90676044:9067 6004:9068 6044:9068 6005:9066 6045:9066 6005:9067 6045:90676005:9068 6045:9068 6006:9066 6046:9066 6006:9067 6046:9067 6006:90686046:9068 6007:9066 6047:9066 6007:9067 6047:9067 6007:9068 6047:90686008:9066 6048:9066 6008:9067 6048:9067 6008:9068 6048:9068 6009:90666049:9066 6009:9067 6049:9067 6009:9068 6049:9068 6010:9066 6050:90666010:9067 6050:9067 6010:9068 6050:9068 6011:9066 6051:9066 6011:90676051:9067 6011:9068 6051:9068 6012:9066 6052:9066 6012:9067 6052:90676012:9068 6052:9068 6013:9066 6053:9066 6013:9067 6053:9067 6013:90686053:9068 6014:9066 6054:9066 6014:9067 6054:9067 6014:9068 6054:90686015:9066 6055:9066 6015:9067 6055:9067 6015:9068 6055:9068 6016:90666056:9066 6016:9067 6056:9067 6016:9068 6056:9068 6017:9066 6057:90666017:9067 6057:9067 6017:9068 6057:9068 6018:9066 6058:9066 6018:90676058:9067 6018:9068 6058:9068 6019:9066 6059:9066 6019:9067 6059:90676019:9068 6059:9068 6020:9066 6060:9066 6020:9067 6060:9067 6020:90686060:9068 6021:9066 6061:9066 6021:9067 6061:9067 6021:9068 6061:90686022:9066 6062:9066 6022:9067 6062:9067 6022:9068 6062:9068 6023:90666063:9066 6023:9067 6063:9067 6023:9068 6063:9068 6024:9066 6064:90666024:9067 6064:9067 6024:9068 6064:9068 6025:9066 6065:9066 6025:90676065:9067 6025:9068 6065:9068 6026:9066 6066:9066 6026:9067 6066:90676026:9068 6066:9068 6027:9066 6067:9066 6027:9067 6067:9067 6027:90686067:9068 6028:9066 6068:9066 6028:9067 6068:9067 6028:9068 6068:90686029:9066 6069:9066 6029:9067 6069:9067 6029:9068 6069:9068 6030:90666070:9066 6030:9067 6070:9067 6030:9068 6070:9068 6031:9066 6071:90666031:9067 6071:9067 6031:9068 6071:9068 6032:9066 6072:9066 6032:90676072:9067 6032:9068 6072:9068 6033:9066 6073:9066 6033:9067 6073:90676033:9068 6073:9068 6034:9066 6074:9066 6034:9067 6074:9067 6034:90686074:9068 6035:9066 6075:9066 6035:9067 6075:9067 6035:9068 6075:90686036:9066 6076:9066 6036:9067 6076:9067 6036:9068 6076:9068 6037:90666077:9066 6037:9067 6077:9067 6037:9068 6077:9068 6038:9066 6078:90666038:9067 6078:9067 6038:9068 6078:9068 6039:9066 6039:9067 6039:90686000:9069 6040:9069 6000:9070 6040:9070 6000:9071 6040:9071 6001:90696041:9069 6001:9070 6041:9070 6001:9071 6041:9071 6002:9069 6042:90696002:9070 6042:9070 6002:9071 6042:9071 6003:9069 6043:9069 6003:90706043:9070 6003:9071 6043:9071 6004:9069 6044:9069 6004:9070 6044:90706004:9071 6044:9071 6005:9069 6045:9069 6005:9070 6045:9070 6005:90716045:9071 6006:9069 6046:9069 6006:9070 6046:9070 6006:9071 6046:90716007:9069 6047:9069 6007:9070 6047:9070 6007:9071 6047:9071 6008:90696048:9069 6008:9070 6048:9070 6008:9071 6048:9071 6009:9069 6049:90696009:9070 6049:9070 6009:9071 6049:9071 6010:9069 6050:9069 6010:90706050:9070 6010:9071 6050:9071 6011:9069 6051:9069 6011:9070 6051:90706011:9071 6051:9071 6012:9069 6052:9069 6012:9070 6052:9070 6012:90716052:9071 6013:9069 6053:9069 6013:9070 6053:9070 6013:9071 6053:90716014:9069 6054:9069 6014:9070 6054:9070 6014:9071 6054:9071 6015:90696055:9069 6015:9070 6055:9070 6015:9071 6055:9071 6016:9069 6056:90696016:9070 6056:9070 6016:9071 6056:9071 6017:9069 6057:9069 6017:90706057:9070 6017:9071 6057:9071 6018:9069 6058:9069 6018:9070 6058:90706018:9071 6058:9071 6019:9069 6059:9069 6019:9070 6059:9070 6019:90716059:9071 6020:9069 6060:9069 6020:9070 6060:9070 6020:9071 6060:90716021:9069 6061:9069 6021:9070 6061:9070 6021:9071 6061:9071 6022:90696062:9069 6022:9070 6062:9070 6022:9071 6062:9071 6023:9069 6063:90696023:9070 6063:9070 6023:9071 6063:9071 6024:9069 6064:9069 6024:90706064:9070 6024:9071 6064:9071 6025:9069 6065:9069 6025:9070 6065:90706025:9071 6065:9071 6026:9069 6066:9069 6026:9070 6066:9070 6026:90716066:9071 6027:9069 6067:9069 6027:9070 6067:9070 6027:9071 6067:90716028:9069 6068:9069 6028:9070 6068:9070 6028:9071 6068:9071 6029:90696069:9069 6029:9070 6069:9070 6029:9071 6069:9071 6030:9069 6070:90696030:9070 6070:9070 6030:9071 6070:9071 6031:9069 6071:9069 6031:90706071:9070 6031:9071 6071:9071 6032:9069 6072:9069 6032:9070 6072:90706032:9071 6072:9071 6033:9069 6073:9069 6033:9070 6073:9070 6033:90716073:9071 6034:9069 6074:9069 6034:9070 6074:9070 6034:9071 6074:90716035:9069 6075:9069 6035:9070 6075:9070 6035:9071 6075:9071 6036:90696076:9069 6036:9070 6076:9070 6036:9071 6076:9071 6037:9069 6077:90696037:9070 6077:9070 6037:9071 6077:9071 6038:9069 6078:9069 6038:90706078:9070 6038:9071 6078:9071 6039:9069 6039:9070 6039:9071 6000:90726040:9072 6000:9073 6040:9073 6000:9074 6040:9074 6001:9072 6041:90726001:9073 6041:9073 6001:9074 6041:9074 6002:9072 6042:9072 6002:90736042:9073 6002:9074 6042:9074 6003:9072 6043:9072 6003:9073 6043:90736003:9074 6043:9074 6004:9072 6044:9072 6004:9073 6044:9073 6004:90746044:9074 6005:9072 6045:9072 6005:9073 6045:9073 6005:9074 6045:90746006:9072 6046:9072 6006:9073 6046:9073 6006:9074 6046:9074 6007:90726047:9072 6007:9073 6047:9073 6007:9074 6047:9074 6008:9072 6048:90726008:9073 6048:9073 6008:9074 6048:9074 6009:9072 6049:9072 6009:90736049:9073 6009:9074 6049:9074 6010:9072 6050:9072 6010:9073 6050:90736010:9074 6050:9074 6011:9072 6051:9072 6011:9073 6051:9073 6011:90746051:9074 6012:9072 6052:9072 6012:9073 6052:9073 6012:9074 6052:90746013:9072 6053:9072 6013:9073 6053:9073 6013:9074 6053:9074 6014:90726054:9072 6014:9073 6054:9073 6014:9074 6054:9074 6015:9072 6055:90726015:9073 6055:9073 6015:9074 6055:9074 6016:9072 6056:9072 6016:90736056:9073 6016:9074 6056:9074 6017:9072 6057:9072 6017:9073 6057:90736017:9074 6057:9074 6018:9072 6058:9072 6018:9073 6058:9073 6018:90746058:9074 6019:9072 6059:9072 6019:9073 6059:9073 6019:9074 6059:90746020:9072 6060:9072 6020:9073 6060:9073 6020:9074 6060:9074 6021:90726061:9072 6021:9073 6061:9073 6021:9074 6061:9074 6022:9072 6062:90726022:9073 6062:9073 6022:9074 6062:9074 6023:9072 6063:9072 6023:90736063:9073 6023:9074 6063:9074 6024:9072 6064:9072 6024:9073 6064:90736024:9074 6064:9074 6025:9072 6065:9072 6025:9073 6065:9073 6025:90746065:9074 6026:9072 6066:9072 6026:9073 6066:9073 6026:9074 6066:90746027:9072 6067:9072 6027:9073 6067:9073 6027:9074 6067:9074 6028:90726068:9072 6028:9073 6068:9073 6028:9074 6068:9074 6029:9072 6069:90726029:9073 6069:9073 6029:9074 6069:9074 6030:9072 6070:9072 6030:90736070:9073 6030:9074 6070:9074 6031:9072 6071:9072 6031:9073 6071:90736031:9074 6071:9074 6032:9072 6072:9072 6032:9073 6072:9073 6032:90746072:9074 6033:9072 6073:9072 6033:9073 6073:9073 6033:9074 6073:90746034:9072 6074:9072 6034:9073 6074:9073 6034:9074 6074:9074 6035:90726075:9072 6035:9073 6075:9073 6035:9074 6075:9074 6036:9072 6076:90726036:9073 6076:9073 6036:9074 6076:9074 6037:9072 6077:9072 6037:90736077:9073 6037:9074 6077:9074 6038:9072 6078:9072 6038:9073 6078:90736038:9074 6078:9074 6039:9072 6039:9073 6039:9074 6000:9075 6040:90756000:9076 6040:9076 6000:9077 6040:9077 6001:9075 6041:9075 6001:90766041:9076 6001:9077 6041:9077 6002:9075 6042:9075 6002:9076 6042:90766002:9077 6042:9077 6003:9075 6043:9075 6003:9076 6043:9076 6003:90776043:9077 6004:9075 6044:9075 6004:9076 6044:9076 6004:9077 6044:90776005:9075 6045:9075 6005:9076 6045:9076 6005:9077 6045:9077 6006:90756046:9075 6006:9076 6046:9076 6006:9077 6046:9077 6007:9075 6047:90756007:9076 6047:9076 6007:9077 6047:9077 6008:9075 6048:9075 6008:90766048:9076 6008:9077 6048:9077 6009:9075 6049:9075 6009:9076 6049:90766009:9077 6049:9077 6010:9075 6050:9075 6010:9076 6050:9076 6010:90776050:9077 6011:9075 6051:9075 6011:9076 6051:9076 6011:9077 6051:90776012:9075 6052:9075 6012:9076 6052:9076 6012:9077 6052:9077 6013:90756053:9075 6013:9076 6053:9076 6013:9077 6053:9077 6014:9075 6054:90756014:9076 6054:9076 6014:9077 6054:9077 6015:9075 6055:9075 6015:90766055:9076 6015:9077 6055:9077 6016:9075 6056:9075 6016:9076 6056:90766016:9077 6056:9077 6017:9075 6057:9075 6017:9076 6057:9076 6017:90776057:9077 6018:9075 6058:9075 6018:9076 6058:9076 6018:9077 6058:90776019:9075 6059:9075 6019:9076 6059:9076 6019:9077 6059:9077 6020:90756060:9075 6020:9076 6060:9076 6020:9077 6060:9077 6021:9075 6061:90756021:9076 6061:9076 6021:9077 6061:9077 6022:9075 6062:9075 6022:90766062:9076 6022:9077 6062:9077 6023:9075 6063:9075 6023:9076 6063:90766023:9077 6063:9077 6024:9075 6064:9075 6024:9076 6064:9076 6024:90776064:9077 6025:9075 6065:9075 6025:9076 6065:9076 6025:9077 6065:90776026:9075 6066:9075 6026:9076 6066:9076 6026:9077 6066:9077 6027:90756067:9075 6027:9076 6067:9076 6027:9077 6067:9077 6028:9075 6068:90756028:9076 6068:9076 6028:9077 6068:9077 6029:9075 6069:9075 6029:90766069:9076 6029:9077 6069:9077 6030:9075 6070:9075 6030:9076 6070:90766030:9077 6070:9077 6031:9075 6071:9075 6031:9076 6071:9076 6031:90776071:9077 6032:9075 6072:9075 6032:9076 6072:9076 6032:9077 6072:90776033:9075 6073:9075 6033:9076 6073:9076 6033:9077 6073:9077 6034:90756074:9075 6034:9076 6074:9076 6034:9077 6074:9077 6035:9075 6075:90756035:9076 6075:9076 6035:9077 6075:9077 6036:9075 6076:9075 6036:90766076:9076 6036:9077 6076:9077 6037:9075 6077:9075 6037:9076 6077:90766037:9077 6077:9077 6038:9075 6078:9075 6038:9076 6078:9076 6038:90776078:9077 6039:9075 6039:9076 6039:9077 6000:9078 6040:9078 6000:90796040:9079 6000:9080 6040:9080 6001:9078 6041:9078 6001:9079 6041:90796001:9080 6041:9080 6002:9078 6042:9078 6002:9079 6042:9079 6002:90806042:9080 6003:9078 6043:9078 6003:9079 6043:9079 6003:9080 6043:90806004:9078 6044:9078 6004:9079 6044:9079 6004:9080 6044:9080 6005:90786045:9078 6005:9079 6045:9079 6005:9080 6045:9080 6006:9078 6046:90786006:9079 6046:9079 6006:9080 6046:9080 6007:9078 6047:9078 6007:90796047:9079 6007:9080 6047:9080 6008:9078 6048:9078 6008:9079 6048:90796008:9080 6048:9080 6009:9078 6049:9078 6009:9079 6049:9079 6009:90806049:9080 6010:9078 6050:9078 6010:9079 6050:9079 6010:9080 6050:90806011:9078 6051:9078 6011:9079 6051:9079 6011:9080 6051:9080 6012:90786052:9078 6012:9079 6052:9079 6012:9080 6052:9080 6013:9078 6053:90786013:9079 6053:9079 6013:9080 6053:9080 6014:9078 6054:9078 6014:90796054:9079 6014:9080 6054:9080 6015:9078 6055:9078 6015:9079 6055:90796015:9080 6055:9080 6016:9078 6056:9078 6016:9079 6056:9079 6016:90806056:9080 6017:9078 6057:9078 6017:9079 6057:9079 6017:9080 6057:90806018:9078 6058:9078 6018:9079 6058:9079 6018:9080 6058:9080 6019:90786059:9078 6019:9079 6059:9079 6019:9080 6059:9080 6020:9078 6060:90786020:9079 6060:9079 6020:9080 6060:9080 6021:9078 6061:9078 6021:90796061:9079 6021:9080 6061:9080 6022:9078 6062:9078 6022:9079 6062:90796022:9080 6062:9080 6023:9078 6063:9078 6023:9079 6063:9079 6023:90806063:9080 6024:9078 6064:9078 6024:9079 6064:9079 6024:9080 6064:90806025:9078 6065:9078 6025:9079 6065:9079 6025:9080 6065:9080 6026:90786066:9078 6026:9079 6066:9079 6026:9080 6066:9080 6027:9078 6067:90786027:9079 6067:9079 6027:9080 6067:9080 6028:9078 6068:9078 6028:90796068:9079 6028:9080 6068:9080 6029:9078 6069:9078 6029:9079 6069:90796029:9080 6069:9080 6030:9078 6070:9078 6030:9079 6070:9079 6030:90806070:9080 6031:9078 6071:9078 6031:9079 6071:9079 6031:9080 6071:90806032:9078 6072:9078 6032:9079 6072:9079 6032:9080 6072:9080 6033:90786073:9078 6033:9079 6073:9079 6033:9080 6073:9080 6034:9078 6074:90786034:9079 6074:9079 6034:9080 6074:9080 6035:9078 6075:9078 6035:90796075:9079 6035:9080 6075:9080 6036:9078 6076:9078 6036:9079 6076:90796036:9080 6076:9080 6037:9078 6077:9078 6037:9079 6077:9079 6037:90806077:9080 6038:9078 6078:9078 6038:9079 6078:9079 6038:9080 6078:90806039:9078 6039:9079 6039:9080 6000:9081 6040:9081 6000:9082 6040:90826000:9083 6040:9083 6001:9081 6041:9081 6001:9082 6041:9082 6001:90836041:9083 6002:9081 6042:9081 6002:9082 6042:9082 6002:9083 6042:90836003:9081 6043:9081 6003:9082 6043:9082 6003:9083 6043:9083 6004:90816044:9081 6004:9082 6044:9082 6004:9083 6044:9083 6005:9081 6045:90816005:9082 6045:9082 6005:9083 6045:9083 6006:9081 6046:9081 6006:90826046:9082 6006:9083 6046:9083 6007:9081 6047:9081 6007:9082 6047:90826007:9083 6047:9083 6008:9081 6048:9081 6008:9082 6048:9082 6008:90836048:9083 6009:9081 6049:9081 6009:9082 6049:9082 6009:9083 6049:90836010:9081 6050:9081 6010:9082 6050:9082 6010:9083 6050:9083 6011:90816051:9081 6011:9082 6051:9082 6011:9083 6051:9083 6012:9081 6052:90816012:9082 6052:9082 6012:9083 6052:9083 6013:9081 6053:9081 6013:90826053:9082 6013:9083 6053:9083 6014:9081 6054:9081 6014:9082 6054:90826014:9083 6054:9083 6015:9081 6055:9081 6015:9082 6055:9082 6015:90836055:9083 6016:9081 6056:9081 6016:9082 6056:9082 6016:9083 6056:90836017:9081 6057:9081 6017:9082 6057:9082 6017:9083 6057:9083 6018:90816058:9081 6018:9082 6058:9082 6018:9083 6058:9083 6019:9081 6059:90816019:9082 6059:9082 6019:9083 6059:9083 6020:9081 6060:9081 6020:90826060:9082 6020:9083 6060:9083 6021:9081 6061:9081 6021:9082 6061:90826021:9083 6061:9083 6022:9081 6062:9081 6022:9082 6062:9082 6022:90836062:9083 6023:9081 6063:9081 6023:9082 6063:9082 6023:9083 6063:90836024:9081 6064:9081 6024:9082 6064:9082 6024:9083 6064:9083 6025:90816065:9081 6025:9082 6065:9082 6025:9083 6065:9083 6026:9081 6066:90816026:9082 6066:9082 6026:9083 6066:9083 6027:9081 6067:9081 6027:90826067:9082 6027:9083 6067:9083 6028:9081 6068:9081 6028:9082 6068:90826028:9083 6068:9083 6029:9081 6069:9081 6029:9082 6069:9082 6029:90836069:9083 6030:9081 6070:9081 6030:9082 6070:9082 6030:9083 6070:90836031:9081 6071:9081 6031:9082 6071:9082 6031:9083 6071:9083 6032:90816072:9081 6032:9082 6072:9082 6032:9083 6072:9083 6033:9081 6073:90816033:9082 6073:9082 6033:9083 6073:9083 6034:9081 6074:9081 6034:90826074:9082 6034:9083 6074:9083 6035:9081 6075:9081 6035:9082 6075:90826035:9083 6075:9083 6036:9081 6076:9081 6036:9082 6076:9082 6036:90836076:9083 6037:9081 6077:9081 6037:9082 6077:9082 6037:9083 6077:90836038:9081 6078:9081 6038:9082 6078:9082 6038:9083 6078:9083 6039:90816039:9082 6039:9083 6000:9084 6040:9084 6000:9085 6040:9085 6000:90866040:9086 6001:9084 6041:9084 6001:9085 6041:9085 6001:9086 6041:90866002:9084 6042:9084 6002:9085 6042:9085 6002:9086 6042:9086 6003:90846043:9084 6003:9085 6043:9085 6003:9086 6043:9086 6004:9084 6044:90846004:9085 6044:9085 6004:9086 6044:9086 6005:9084 6045:9084 6005:90856045:9085 6005:9086 6045:9086 6006:9084 6046:9084 6006:9085 6046:90856006:9086 6046:9086 6007:9084 6047:9084 6007:9085 6047:9085 6007:90866047:9086 6008:9084 6048:9084 6008:9085 6048:9085 6008:9086 6048:90866009:9084 6049:9084 6009:9085 6049:9085 6009:9086 6049:9086 6010:90846050:9084 6010:9085 6050:9085 6010:9086 6050:9086 6011:9084 6051:90846011:9085 6051:9085 6011:9086 6051:9086 6012:9084 6052:9084 6012:90856052:9085 6012:9086 6052:9086 6013:9084 6053:9084 6013:9085 6053:90856013:9086 6053:9086 6014:9084 6054:9084 6014:9085 6054:9085 6014:90866054:9086 6015:9084 6055:9084 6015:9085 6055:9085 6015:9086 6055:90866016:9084 6056:9084 6016:9085 6056:9085 6016:9086 6056:9086 6017:90846057:9084 6017:9085 6057:9085 6017:9086 6057:9086 6018:9084 6058:90846018:9085 6058:9085 6018:9086 6058:9086 6019:9084 6059:9084 6019:90856059:9085 6019:9086 6059:9086 6020:9084 6060:9084 6020:9085 6060:90856020:9086 6060:9086 6021:9084 6061:9084 6021:9085 6061:9085 6021:90866061:9086 6022:9084 6062:9084 6022:9085 6062:9085 6022:9086 6062:90866023:9084 6063:9084 6023:9085 6063:9085 6023:9086 6063:9086 6024:90846064:9084 6024:9085 6064:9085 6024:9086 6064:9086 6025:9084 6065:90846025:9085 6065:9085 6025:9086 6065:9086 6026:9084 6066:9084 6026:90856066:9085 6026:9086 6066:9086 6027:9084 6067:9084 6027:9085 6067:90856027:9086 6067:9086 6028:9084 6068:9084 6028:9085 6068:9085 6028:90866068:9086 6029:9084 6069:9084 6029:9085 6069:9085 6029:9086 6069:90866030:9084 6070:9084 6030:9085 6070:9085 6030:9086 6070:9086 6031:90846071:9084 6031:9085 6071:9085 6031:9086 6071:9086 6032:9084 6072:90846032:9085 6072:9085 6032:9086 6072:9086 6033:9084 6073:9084 6033:90856073:9085 6033:9086 6073:9086 6034:9084 6074:9084 6034:9085 6074:90856034:9086 6074:9086 6035:9084 6075:9084 6035:9085 6075:9085 6035:90866075:9086 6036:9084 6076:9084 6036:9085 6076:9085 6036:9086 6076:90866037:9084 6077:9084 6037:9085 6077:9085 6037:9086 6077:9086 6038:90846078:9084 6038:9085 6078:9085 6038:9086 6078:9086 6039:9084 6039:90856039:9086 6000:9087 6040:9087 6000:9088 6040:9088 6000:9089 6040:90896001:9087 6041:9087 6001:9088 6041:9088 6001:9089 6041:9089 6002:90876042:9087 6002:9088 6042:9088 6002:9089 6042:9089 6003:9087 6043:90876003:9088 6043:9088 6003:9089 6043:9089 6004:9087 6044:9087 6004:90886044:9088 6004:9089 6044:9089 6005:9087 6045:9087 6005:9088 6045:90886005:9089 6045:9089 6006:9087 6046:9087 6006:9088 6046:9088 6006:90896046:9089 6007:9087 6047:9087 6007:9088 6047:9088 6007:9089 6047:90896008:9087 6048:9087 6008:9088 6048:9088 6008:9089 6048:9089 6009:90876049:9087 6009:9088 6049:9088 6009:9089 6049:9089 6010:9087 6050:90876010:9088 6050:9088 6010:9089 6050:9089 6011:9087 6051:9087 6011:90886051:9088 6011:9089 6051:9089 6012:9087 6052:9087 6012:9088 6052:90886012:9089 6052:9089 6013:9087 6053:9087 6013:9088 6053:9088 6013:90896053:9089 6014:9087 6054:9087 6014:9088 6054:9088 6014:9089 6054:90896015:9087 6055:9087 6015:9088 6055:9088 6015:9089 6055:9089 6016:90876056:9087 6016:9088 6056:9088 6016:9089 6056:9089 6017:9087 6057:90876017:9088 6057:9088 6017:9089 6057:9089 6018:9087 6058:9087 6018:90886058:9088 6018:9089 6058:9089 6019:9087 6059:9087 6019:9088 6059:90886019:9089 6059:9089 6020:9087 6060:9087 6020:9088 6060:9088 6020:90896060:9089 6021:9087 6061:9087 6021:9088 6061:9088 6021:9089 6061:90896022:9087 6062:9087 6022:9088 6062:9088 6022:9089 6062:9089 6023:90876063:9087 6023:9088 6063:9088 6023:9089 6063:9089 6024:9087 6064:90876024:9088 6064:9088 6024:9089 6064:9089 6025:9087 6065:9087 6025:90886065:9088 6025:9089 6065:9089 6026:9087 6066:9087 6026:9088 6066:90886026:9089 6066:9089 6027:9087 6067:9087 6027:9088 6067:9088 6027:90896067:9089 6028:9087 6068:9087 6028:9088 6068:9088 6028:9089 6068:90896029:9087 6069:9087 6029:9088 6069:9088 6029:9089 6069:9089 6030:90876070:9087 6030:9088 6070:9088 6030:9089 6070:9089 6031:9087 6071:90876031:9088 6071:9088 6031:9089 6071:9089 6032:9087 6072:9087 6032:90886072:9088 6032:9089 6072:9089 6033:9087 6073:9087 6033:9088 6073:90886033:9089 6073:9089 6034:9087 6074:9087 6034:9088 6074:9088 6034:90896074:9089 6035:9087 6075:9087 6035:9088 6075:9088 6035:9089 6075:90896036:9087 6076:9087 6036:9088 6076:9088 6036:9089 6076:9089 6037:90876077:9087 6037:9088 6077:9088 6037:9089 6077:9089 6038:9087 6078:90876038:9088 6078:9088 6038:9089 6078:9089 6039:9087 6039:9088 6039:90896000:9090 6040:9090 6000:9091 6040:9091 6000:9092 6040:9092 6001:90906041:9090 6001:9091 6041:9091 6001:9092 6041:9092 6002:9090 6042:90906002:9091 6042:9091 6002:9092 6042:9092 6003:9090 6043:9090 6003:90916043:9091 6003:9092 6043:9092 6004:9090 6044:9090 6004:9091 6044:90916004:9092 6044:9092 6005:9090 6045:9090 6005:9091 6045:9091 6005:90926045:9092 6006:9090 6046:9090 6006:9091 6046:9091 6006:9092 6046:90926007:9090 6047:9090 6007:9091 6047:9091 6007:9092 6047:9092 6008:90906048:9090 6008:9091 6048:9091 6008:9092 6048:9092 6009:9090 6049:90906009:9091 6049:9091 6009:9092 6049:9092 6010:9090 6050:9090 6010:90916050:9091 6010:9092 6050:9092 6011:9090 6051:9090 6011:9091 6051:90916011:9092 6051:9092 6012:9090 6052:9090 6012:9091 6052:9091 6012:90926052:9092 6013:9090 6053:9090 6013:9091 6053:9091 6013:9092 6053:90926014:9090 6054:9090 6014:9091 6054:9091 6014:9092 6054:9092 6015:90906055:9090 6015:9091 6055:9091 6015:9092 6055:9092 6016:9090 6056:90906016:9091 6056:9091 6016:9092 6056:9092 6017:9090 6057:9090 6017:90916057:9091 6017:9092 6057:9092 6018:9090 6058:9090 6018:9091 6058:90916018:9092 6058:9092 6019:9090 6059:9090 6019:9091 6059:9091 6019:90926059:9092 6020:9090 6060:9090 6020:9091 6060:9091 6020:9092 6060:90926021:9090 6061:9090 6021:9091 6061:9091 6021:9092 6061:9092 6022:90906062:9090 6022:9091 6062:9091 6022:9092 6062:9092 6023:9090 6063:90906023:9091 6063:9091 6023:9092 6063:9092 6024:9090 6064:9090 6024:90916064:9091 6024:9092 6064:9092 6025:9090 6065:9090 6025:9091 6065:90916025:9092 6065:9092 6026:9090 6066:9090 6026:9091 6066:9091 6026:90926066:9092 6027:9090 6067:9090 6027:9091 6067:9091 6027:9092 6067:90926028:9090 6068:9090 6028:9091 6068:9091 6028:9092 6068:9092 6029:90906069:9090 6029:9091 6069:9091 6029:9092 6069:9092 6030:9090 6070:90906030:9091 6070:9091 6030:9092 6070:9092 6031:9090 6071:9090 6031:90916071:9091 6031:9092 6071:9092 6032:9090 6072:9090 6032:9091 6072:90916032:9092 6072:9092 6033:9090 6073:9090 6033:9091 6073:9091 6033:90926073:9092 6034:9090 6074:9090 6034:9091 6074:9091 6034:9092 6074:90926035:9090 6075:9090 6035:9091 6075:9091 6035:9092 6075:9092 6036:90906076:9090 6036:9091 6076:9091 6036:9092 6076:9092 6037:9090 6077:90906037:9091 6077:9091 6037:9092 6077:9092 6038:9090 6078:9090 6038:90916078:9091 6038:9092 6078:9092 6039:9090 6039:9091 6039:9092 6000:90936040:9093 6000:9094 6040:9094 6000:9095 6040:9095 6001:9093 6041:90936001:9094 6041:9094 6001:9095 6041:9095 6002:9093 6042:9093 6002:90946042:9094 6002:9095 6042:9095 6003:9093 6043:9093 6003:9094 6043:90946003:9095 6043:9095 6004:9093 6044:9093 6004:9094 6044:9094 6004:90956044:9095 6005:9093 6045:9093 6005:9094 6045:9094 6005:9095 6045:90956006:9093 6046:9093 6006:9094 6046:9094 6006:9095 6046:9095 6007:90936047:9093 6007:9094 6047:9094 6007:9095 6047:9095 6008:9093 6048:90936008:9094 6048:9094 6008:9095 6048:9095 6009:9093 6049:9093 6009:90946049:9094 6009:9095 6049:9095 6010:9093 6050:9093 6010:9094 6050:90946010:9095 6050:9095 6011:9093 6051:9093 6011:9094 6051:9094 6011:90956051:9095 6012:9093 6052:9093 6012:9094 6052:9094 6012:9095 6052:90956013:9093 6053:9093 6013:9094 6053:9094 6013:9095 6053:9095 6014:90936054:9093 6014:9094 6054:9094 6014:9095 6054:9095 6015:9093 6055:90936015:9094 6055:9094 6015:9095 6055:9095 6016:9093 6056:9093 6016:90946056:9094 6016:9095 6056:9095 6017:9093 6057:9093 6017:9094 6057:90946017:9095 6057:9095 6018:9093 6058:9093 6018:9094 6058:9094 6018:90956058:9095 6019:9093 6059:9093 6019:9094 6059:9094 6019:9095 6059:90956020:9093 6060:9093 6020:9094 6060:9094 6020:9095 6060:9095 6021:90936061:9093 6021:9094 6061:9094 6021:9095 6061:9095 6022:9093 6062:90936022:9094 6062:9094 6022:9095 6062:9095 6023:9093 6063:9093 6023:90946063:9094 6023:9095 6063:9095 6024:9093 6064:9093 6024:9094 6064:90946024:9095 6064:9095 6025:9093 6065:9093 6025:9094 6065:9094 6025:90956065:9095 6026:9093 6066:9093 6026:9094 6066:9094 6026:9095 6066:90956027:9093 6067:9093 6027:9094 6067:9094 6027:9095 6067:9095 6028:90936068:9093 6028:9094 6068:9094 6028:9095 6068:9095 6029:9093 6069:90936029:9094 6069:9094 6029:9095 6069:9095 6030:9093 6070:9093 6030:90946070:9094 6030:9095 6070:9095 6031:9093 6071:9093 6031:9094 6071:90946031:9095 6071:9095 6032:9093 6072:9093 6032:9094 6072:9094 6032:90956072:9095 6033:9093 6073:9093 6033:9094 6073:9094 6033:9095 6073:90956034:9093 6074:9093 6034:9094 6074:9094 6034:9095 6074:9095 6035:90936075:9093 6035:9094 6075:9094 6035:9095 6075:9095 6036:9093 6076:90936036:9094 6076:9094 6036:9095 6076:9095 6037:9093 6077:9093 6037:90946077:9094 6037:9095 6077:9095 6038:9093 6078:9093 6038:9094 6078:90946038:9095 6078:9095 6039:9093 6039:9094 6039:9095 6000:9096 6040:90966000:9097 6040:9097 6000:9098 6040:9098 6001:9096 6041:9096 6001:90976041:9097 6001:9098 6041:9098 6002:9096 6042:9096 6002:9097 6042:90976002:9098 6042:9098 6003:9096 6043:9096 6003:9097 6043:9097 6003:90986043:9098 6004:9096 6044:9096 6004:9097 6044:9097 6004:9098 6044:90986005:9096 6045:9096 6005:9097 6045:9097 6005:9098 6045:9098 6006:90966046:9096 6006:9097 6046:9097 6006:9098 6046:9098 6007:9096 6047:90966007:9097 6047:9097 6007:9098 6047:9098 6008:9096 6048:9096 6008:90976048:9097 6008:9098 6048:9098 6009:9096 6049:9096 6009:9097 6049:90976009:9098 6049:9098 6010:9096 6050:9096 6010:9097 6050:9097 6010:90986050:9098 6011:9096 6051:9096 6011:9097 6051:9097 6011:9098 6051:90986012:9096 6052:9096 6012:9097 6052:9097 6012:9098 6052:9098 6013:90966053:9096 6013:9097 6053:9097 6013:9098 6053:9098 6014:9096 6054:90966014:9097 6054:9097 6014:9098 6054:9098 6015:9096 6055:9096 6015:90976055:9097 6015:9098 6055:9098 6016:9096 6056:9096 6016:9097 6056:90976016:9098 6056:9098 6017:9096 6057:9096 6017:9097 6057:9097 6017:90986057:9098 6018:9096 6058:9096 6018:9097 6058:9097 6018:9098 6058:90986019:9096 6059:9096 6019:9097 6059:9097 6019:9098 6059:9098 6020:90966060:9096 6020:9097 6060:9097 6020:9098 6060:9098 6021:9096 6061:90966021:9097 6061:9097 6021:9098 6061:9098 6022:9096 6062:9096 6022:90976062:9097 6022:9098 6062:9098 6023:9096 6063:9096 6023:9097 6063:90976023:9098 6063:9098 6024:9096 6064:9096 6024:9097 6064:9097 6024:90986064:9098 6025:9096 6065:9096 6025:9097 6065:9097 6025:9098 6065:90986026:9096 6066:9096 6026:9097 6066:9097 6026:9098 6066:9098 6027:90966067:9096 6027:9097 6067:9097 6027:9098 6067:9098 6028:9096 6068:90966028:9097 6068:9097 6028:9098 6068:9098 6029:9096 6069:9096 6029:90976069:9097 6029:9098 6069:9098 6030:9096 6070:9096 6030:9097 6070:90976030:9098 6070:9098 6031:9096 6071:9096 6031:9097 6071:9097 6031:90986071:9098 6032:9096 6072:9096 6032:9097 6072:9097 6032:9098 6072:90986033:9096 6073:9096 6033:9097 6073:9097 6033:9098 6073:9098 6034:90966074:9096 6034:9097 6074:9097 6034:9098 6074:9098 6035:9096 6075:90966035:9097 6075:9097 6035:9098 6075:9098 6036:9096 6076:9096 6036:90976076:9097 6036:9098 6076:9098 6037:9096 6077:9096 6037:9097 6077:90976037:9098 6077:9098 6038:9096 6078:9096 6038:9097 6078:9097 6038:90986078:9098 6039:9096 6039:9097 6039:9098 6000:9099 6040:9099 6000:91006040:9100 6000:9101 6040:9101 6001:9099 6041:9099 6001:9100 6041:91006001:9101 6041:9101 6002:9099 6042:9099 6002:9100 6042:9100 6002:91016042:9101 6003:9099 6043:9099 6003:9100 6043:9100 6003:9101 6043:91016004:9099 6044:9099 6004:9100 6044:9100 6004:9101 6044:9101 6005:90996045:9099 6005:9100 6045:9100 6005:9101 6045:9101 6006:9099 6046:90996006:9100 6046:9100 6006:9101 6046:9101 6007:9099 6047:9099 6007:91006047:9100 6007:9101 6047:9101 6008:9099 6048:9099 6008:9100 6048:91006008:9101 6048:9101 6009:9099 6049:9099 6009:9100 6049:9100 6009:91016049:9101 6010:9099 6050:9099 6010:9100 6050:9100 6010:9101 6050:91016011:9099 6051:9099 6011:9100 6051:9100 6011:9101 6051:9101 6012:90996052:9099 6012:9100 6052:9100 6012:9101 6052:9101 6013:9099 6053:90996013:9100 6053:9100 6013:9101 6053:9101 6014:9099 6054:9099 6014:91006054:9100 6014:9101 6054:9101 6015:9099 6055:9099 6015:9100 6055:91006015:9101 6055:9101 6016:9099 6056:9099 6016:9100 6056:9100 6016:91016056:9101 6017:9099 6057:9099 6017:9100 6057:9100 6017:9101 6057:91016018:9099 6058:9099 6018:9100 6058:9100 6018:9101 6058:9101 6019:90996059:9099 6019:9100 6059:9100 6019:9101 6059:9101 6020:9099 6060:90996020:9100 6060:9100 6020:9101 6060:9101 6021:9099 6061:9099 6021:91006061:9100 6021:9101 6061:9101 6022:9099 6062:9099 6022:9100 6062:91006022:9101 6062:9101 6023:9099 6063:9099 6023:9100 6063:9100 6023:91016063:9101 6024:9099 6064:9099 6024:9100 6064:9100 6024:9101 6064:91016025:9099 6065:9099 6025:9100 6065:9100 6025:9101 6065:9101 6026:90996066:9099 6026:9100 6066:9100 6026:9101 6066:9101 6027:9099 6067:90996027:9100 6067:9100 6027:9101 6067:9101 6028:9099 6068:9099 6028:91006068:9100 6028:9101 6068:9101 6029:9099 6069:9099 6029:9100 6069:91006029:9101 6069:9101 6030:9099 6070:9099 6030:9100 6070:9100 6030:91016070:9101 6031:9099 6071:9099 6031:9100 6071:9100 6031:9101 6071:91016032:9099 6072:9099 6032:9100 6072:9100 6032:9101 6072:9101 6033:90996073:9099 6033:9100 6073:9100 6033:9101 6073:9101 6034:9099 6074:90996034:9100 6074:9100 6034:9101 6074:9101 6035:9099 6075:9099 6035:91006075:9100 6035:9101 6075:9101 6036:9099 6076:9099 6036:9100 6076:91006036:9101 6076:9101 6037:9099 6077:9099 6037:9100 6077:9100 6037:91016077:9101 6038:9099 6078:9099 6038:9100 6078:9100 6038:9101 6078:91016039:9099 6039:9100 6039:9101 6000:9102 6040:9102 6000:9103 6040:91036000:9104 6040:9104 6001:9102 6041:9102 6001:9103 6041:9103 6001:91046041:9104 6002:9102 6042:9102 6002:9103 6042:9103 6002:9104 6042:91046003:9102 6043:9102 6003:9103 6043:9103 6003:9104 6043:9104 6004:91026044:9102 6004:9103 6044:9103 6004:9104 6044:9104 6005:9102 6045:91026005:9103 6045:9103 6005:9104 6045:9104 6006:9102 6046:9102 6006:91036046:9103 6006:9104 6046:9104 6007:9102 6047:9102 6007:9103 6047:91036007:9104 6047:9104 6008:9102 6048:9102 6008:9103 6048:9103 6008:91046048:9104 6009:9102 6049:9102 6009:9103 6049:9103 6009:9104 6049:91046010:9102 6050:9102 6010:9103 6050:9103 6010:9104 6050:9104 6011:91026051:9102 6011:9103 6051:9103 6011:9104 6051:9104 6012:9102 6052:91026012:9103 6052:9103 6012:9104 6052:9104 6013:9102 6053:9102 6013:91036053:9103 6013:9104 6053:9104 6014:9102 6054:9102 6014:9103 6054:91036014:9104 6054:9104 6015:9102 6055:9102 6015:9103 6055:9103 6015:91046055:9104 6016:9102 6056:9102 6016:9103 6056:9103 6016:9104 6056:91046017:9102 6057:9102 6017:9103 6057:9103 6017:9104 6057:9104 6018:91026058:9102 6018:9103 6058:9103 6018:9104 6058:9104 6019:9102 6059:91026019:9103 6059:9103 6019:9104 6059:9104 6020:9102 6060:9102 6020:91036060:9103 6020:9104 6060:9104 6021:9102 6061:9102 6021:9103 6061:91036021:9104 6061:9104 6022:9102 6062:9102 6022:9103 6062:9103 6022:91046062:9104 6023:9102 6063:9102 6023:9103 6063:9103 6023:9104 6063:91046024:9102 6064:9102 6024:9103 6064:9103 6024:9104 6064:9104 6025:91026065:9102 6025:9103 6065:9103 6025:9104 6065:9104 6026:9102 6066:91026026:9103 6066:9103 6026:9104 6066:9104 6027:9102 6067:9102 6027:91036067:9103 6027:9104 6067:9104 6028:9102 6068:9102 6028:9103 6068:91036028:9104 6068:9104 6029:9102 6069:9102 6029:9103 6069:9103 6029:91046069:9104 6030:9102 6070:9102 6030:9103 6070:9103 6030:9104 6070:91046031:9102 6071:9102 6031:9103 6071:9103 6031:9104 6071:9104 6032:91026072:9102 6032:9103 6072:9103 6032:9104 6072:9104 6033:9102 6073:91026033:9103 6073:9103 6033:9104 6073:9104 6034:9102 6074:9102 6034:91036074:9103 6034:9104 6074:9104 6035:9102 6075:9102 6035:9103 6075:91036035:9104 6075:9104 6036:9102 6076:9102 6036:9103 6076:9103 6036:91046076:9104 6037:9102 6077:9102 6037:9103 6077:9103 6037:9104 6077:91046038:9102 6078:9102 6038:9103 6078:9103 6038:9104 6078:9104 6039:91026039:9103 6039:9104 6000:9105 6040:9105 — — — — 6001:9105 6041:91056002:9105 6042:9105 6003:9105 6043:9105 6004:9105 6044:9105 6005:91056045:9105 6006:9105 6046:9105 6007:9105 6047:9105 6008:9105 6048:91056009:9105 6049:9105 6010:9105 6050:9105 6011:9105 6051:9105 6012:91056052:9105 6013:9105 6053:9105 6014:9105 6054:9105 6015:9105 6055:91056016:9105 6056:9105 6017:9105 6057:9105 6018:9105 6058:9105 6019:91056059:9105 6020:9105 6060:9105 6021:9105 6061:9105 6022:9105 6062:91056023:9105 6063:9105 6024:9105 6064:9105 6025:9105 6065:9105 6026:91056066:9105 6027:9105 6067:9105 6028:9105 6068:9105 6029:9105 6069:91056030:9105 6070:9105 6031:9105 6071:9105 6032:9105 6072:9105 6033:91056073:9105 6034:9105 6074:9105 6035:9105 6075:9105 6036:9105 6076:91056037:9105 6077:9105 6038:9105 6078:9105 6039:9105

TABLE E Example combinations of a compound X with a compound Y. X:Y X:YX:Y X:Y X:Y X:Y 8000:9000 8000:9001 8000:9002 8000:9003 8000:90048000:9005 8001:9000 8001:9001 8001:9002 8001:9003 8001:9004 8001:90058002:9000 8002:9001 8002:9002 8002:9003 8002:9004 8002:9005 8003:90008003:9001 8003:9002 8003:9003 8003:9004 8003:9005 8004:9000 8004:90018004:9002 8004:9003 8004:9004 8004:9005 8005:9000 8005:9001 8005:90028005:9003 8005:9004 8005:9005 8006:9000 8006:9001 8006:9002 8006:90038006:9004 8006:9005 8007:9000 8007:9001 8007:9002 8007:9003 8007:90048007:9005 8008:9000 8008:9001 8008:9002 8008:9003 8008:9004 8008:90058009:9000 8009:9001 8009:9002 8009:9003 8009:9004 8009:9005 8010:90008010:9001 8010:9002 8010:9003 8010:9004 8010:9005 8011:9000 8011:90018011:9002 8011:9003 8011:9004 8011:9005 8012:9000 8012:9001 8012:90028012:9003 8012:9004 8012:9005 8013:9000 8013:9001 8013:9002 8013:90038013:9004 8013:9005 8014:9000 8014:9001 8014:9002 8014:9003 8014:90048014:9005 8015:9000 8015:9001 8015:9002 8015:9003 8015:9004 8015:90058016:9000 8016:9001 8016:9002 8016:9003 8016:9004 8016:9005 8000:90068000:9007 8000:9008 8000:9009 8000:9010 8000:9011 8001:9006 8001:90078001:9008 8001:9009 8001:9010 8001:9011 8002:9006 8002:9007 8002:90088002:9009 8002:9010 8002:9011 8003:9006 8003:9007 8003:9008 8003:90098003:9010 8003:9011 8004:9006 8004:9007 8004:9008 8004:9009 8004:90108004:9011 8005:9006 8005:9007 8005:9008 8005:9009 8005:9010 8005:90118006:9006 8006:9007 8006:9008 8006:9009 8006:9010 8006:9011 8007:90068007:9007 8007:9008 8007:9009 8007:9010 8007:9011 8008:9006 8008:90078008:9008 8008:9009 8008:9010 8008:9011 8009:9006 8009:9007 8009:90088009:9009 8009:9010 8009:9011 8010:9006 8010:9007 8010:9008 8010:90098010:9010 8010:9011 8011:9006 8011:9007 8011:9008 8011:9009 8011:90108011:9011 8012:9006 8012:9007 8012:9008 8012:9009 8012:9010 8012:90118013:9006 8013:9007 8013:9008 8013:9009 8013:9010 8013:9011 8014:90068014:9007 8014:9008 8014:9009 8014:9010 8014:9011 8015:9006 8015:90078015:9008 8015:9009 8015:9010 8015:9011 8016:9006 8016:9007 8016:90088016:9009 8016:9010 8016:9011 8000:9012 8000:9013 8000:9014 8000:90158000:9016 8000:9017 8001:9012 8001:9013 8001:9014 8001:9015 8001:90168001:9017 8002:9012 8002:9013 8002:9014 8002:9015 8002:9016 8002:90178003:9012 8003:9013 8003:9014 8003:9015 8003:9016 8003:9017 8004:90128004:9013 8004:9014 8004:9015 8004:9016 8004:9017 8005:9012 8005:90138005:9014 8005:9015 8005:9016 8005:9017 8006:9012 8006:9013 8006:90148006:9015 8006:9016 8006:9017 8007:9012 8007:9013 8007:9014 8007:90158007:9016 8007:9017 8008:9012 8008:9013 8008:9014 8008:9015 8008:90168008:9017 8009:9012 8009:9013 8009:9014 8009:9015 8009:9016 8009:90178010:9012 8010:9013 8010:9014 8010:9015 8010:9016 8010:9017 8011:90128011:9013 8011:9014 8011:9015 8011:9016 8011:9017 8012:9012 8012:90138012:9014 8012:9015 8012:9016 8012:9017 8013:9012 8013:9013 8013:90148013:9015 8013:9016 8013:9017 8014:9012 8014:9013 8014:9014 8014:90158014:9016 8014:9017 8015:9012 8015:9013 8015:9014 8015:9015 8015:90168015:9017 8016:9012 8016:9013 8016:9014 8016:9015 8016:9016 8016:90178000:9018 8000:9019 8000:9020 8000:9021 8000:9022 8000:9023 8001:90188001:9019 8001:9020 8001:9021 8001:9022 8001:9023 8002:9018 8002:90198002:9020 8002:9021 8002:9022 8002:9023 8003:9018 8003:9019 8003:90208003:9021 8003:9022 8003:9023 8004:9018 8004:9019 8004:9020 8004:90218004:9022 8004:9023 8005:9018 8005:9019 8005:9020 8005:9021 8005:90228005:9023 8006:9018 8006:9019 8006:9020 8006:9021 8006:9022 8006:90238007:9018 8007:9019 8007:9020 8007:9021 8007:9022 8007:9023 8008:90188008:9019 8008:9020 8008:9021 8008:9022 8008:9023 8009:9018 8009:90198009:9020 8009:9021 8009:9022 8009:9023 8010:9018 8010:9019 8010:90208010:9021 8010:9022 8010:9023 8011:9018 8011:9019 8011:9020 8011:90218011:9022 8011:9023 8012:9018 8012:9019 8012:9020 8012:9021 8012:90228012:9023 8013:9018 8013:9019 8013:9020 8013:9021 8013:9022 8013:90238014:9018 8014:9019 8014:9020 8014:9021 8014:9022 8014:9023 8015:90188015:9019 8015:9020 8015:9021 8015:9022 8015:9023 8016:9018 8016:90198016:9020 8016:9021 8016:9022 8016:9023 8000:9024 8000:9025 8000:90268000:9027 8000:9028 8000:9029 8001:9024 8001:9025 8001:9026 8001:90278001:9028 8001:9029 8002:9024 8002:9025 8002:9026 8002:9027 8002:90288002:9029 8003:9024 8003:9025 8003:9026 8003:9027 8003:9028 8003:90298004:9024 8004:9025 8004:9026 8004:9027 8004:9028 8004:9029 8005:90248005:9025 8005:9026 8005:9027 8005:9028 8005:9029 8006:9024 8006:90258006:9026 8006:9027 8006:9028 8006:9029 8007:9024 8007:9025 8007:90268007:9027 8007:9028 8007:9029 8008:9024 8008:9025 8008:9026 8008:90278008:9028 8008:9029 8009:9024 8009:9025 8009:9026 8009:9027 8009:90288009:9029 8010:9024 8010:9025 8010:9026 8010:9027 8010:9028 8010:90298011:9024 8011:9025 8011:9026 8011:9027 8011:9028 8011:9029 8012:90248012:9025 8012:9026 8012:9027 8012:9028 8012:9029 8013:9024 8013:90258013:9026 8013:9027 8013:9028 8013:9029 8014:9024 8014:9025 8014:90268014:9027 8014:9028 8014:9029 8015:9024 8015:9025 8015:9026 8015:90278015:9028 8015:9029 8016:9024 8016:9025 8016:9026 8016:9027 8016:90288016:9029 8000:9030 8000:9031 8000:9032 8000:9033 8000:9034 8000:90358001:9030 8001:9031 8001:9032 8001:9033 8001:9034 8001:9035 8002:90308002:9031 8002:9032 8002:9033 8002:9034 8002:9035 8003:9030 8003:90318003:9032 8003:9033 8003:9034 8003:9035 8004:9030 8004:9031 8004:90328004:9033 8004:9034 8004:9035 8005:9030 8005:9031 8005:9032 8005:90338005:9034 8005:9035 8006:9030 8006:9031 8006:9032 8006:9033 8006:90348006:9035 8007:9030 8007:9031 8007:9032 8007:9033 8007:9034 8007:90358008:9030 8008:9031 8008:9032 8008:9033 8008:9034 8008:9035 8009:90308009:9031 8009:9032 8009:9033 8009:9034 8009:9035 8010:9030 8010:90318010:9032 8010:9033 8010:9034 8010:9035 8011:9030 8011:9031 8011:90328011:9033 8011:9034 8011:9035 8012:9030 8012:9031 8012:9032 8012:90338012:9034 8012:9035 8013:9030 8013:9031 8013:9032 8013:9033 8013:90348013:9035 8014:9030 8014:9031 8014:9032 8014:9033 8014:9034 8014:90358015:9030 8015:9031 8015:9032 8015:9033 8015:9034 8015:9035 8016:90308016:9031 8016:9032 8016:9033 8016:9034 8016:9035 8000:9036 8000:90378000:9038 8000:9039 8000:9040 8000:9041 8001:9036 8001:9037 8001:90388001:9039 8001:9040 8001:9041 8002:9036 8002:9037 8002:9038 8002:90398002:9040 8002:9041 8003:9036 8003:9037 8003:9038 8003:9039 8003:90408003:9041 8004:9036 8004:9037 8004:9038 8004:9039 8004:9040 8004:90418005:9036 8005:9037 8005:9038 8005:9039 8005:9040 8005:9041 8006:90368006:9037 8006:9038 8006:9039 8006:9040 8006:9041 8007:9036 8007:90378007:9038 8007:9039 8007:9040 8007:9041 8008:9036 8008:9037 8008:90388008:9039 8008:9040 8008:9041 8009:9036 8009:9037 8009:9038 8009:90398009:9040 8009:9041 8010:9036 8010:9037 8010:9038 8010:9039 8010:90408010:9041 8011:9036 8011:9037 8011:9038 8011:9039 8011:9040 8011:90418012:9036 8012:9037 8012:9038 8012:9039 8012:9040 8012:9041 8013:90368013:9037 8013:9038 8013:9039 8013:9040 8013:9041 8014:9036 8014:90378014:9038 8014:9039 8014:9040 8014:9041 8015:9036 8015:9037 8015:90388015:9039 8015:9040 8015:9041 8016:9036 8016:9037 8016:9038 8016:90398016:9040 8016:9041 8000:9042 8000:9043 8000:9044 8000:9045 8000:90468000:9047 8001:9042 8001:9043 8001:9044 8001:9045 8001:9046 8001:90478002:9042 8002:9043 8002:9044 8002:9045 8002:9046 8002:9047 8003:90428003:9043 8003:9044 8003:9045 8003:9046 8003:9047 8004:9042 8004:90438004:9044 8004:9045 8004:9046 8004:9047 8005:9042 8005:9043 8005:90448005:9045 8005:9046 8005:9047 8006:9042 8006:9043 8006:9044 8006:90458006:9046 8006:9047 8007:9042 8007:9043 8007:9044 8007:9045 8007:90468007:9047 8008:9042 8008:9043 8008:9044 8008:9045 8008:9046 8008:90478009:9042 8009:9043 8009:9044 8009:9045 8009:9046 8009:9047 8010:90428010:9043 8010:9044 8010:9045 8010:9046 8010:9047 8011:9042 8011:90438011:9044 8011:9045 8011:9046 8011:9047 8012:9042 8012:9043 8012:90448012:9045 8012:9046 8012:9047 8013:9042 8013:9043 8013:9044 8013:90458013:9046 8013:9047 8014:9042 8014:9043 8014:9044 8014:9045 8014:90468014:9047 8015:9042 8015:9043 8015:9044 8015:9045 8015:9046 8015:90478016:9042 8016:9043 8016:9044 8016:9045 8016:9046 8016:9047 8000:90488000:9049 8000:9050 8000:9051 8000:9052 8000:9053 8001:9048 8001:90498001:9050 8001:9051 8001:9052 8001:9053 8002:9048 8002:9049 8002:90508002:9051 8002:9052 8002:9053 8003:9048 8003:9049 8003:9050 8003:90518003:9052 8003:9053 8004:9048 8004:9049 8004:9050 8004:9051 8004:90528004:9053 8005:9048 8005:9049 8005:9050 8005:9051 8005:9052 8005:90538006:9048 8006:9049 8006:9050 8006:9051 8006:9052 8006:9053 8007:90488007:9049 8007:9050 8007:9051 8007:9052 8007:9053 8008:9048 8008:90498008:9050 8008:9051 8008:9052 8008:9053 8009:9048 8009:9049 8009:90508009:9051 8009:9052 8009:9053 8010:9048 8010:9049 8010:9050 8010:90518010:9052 8010:9053 8011:9048 8011:9049 8011:9050 8011:9051 8011:90528011:9053 8012:9048 8012:9049 8012:9050 8012:9051 8012:9052 8012:90538013:9048 8013:9049 8013:9050 8013:9051 8013:9052 8013:9053 8014:90488014:9049 8014:9050 8014:9051 8014:9052 8014:9053 8015:9048 8015:90498015:9050 8015:9051 8015:9052 8015:9053 8016:9048 8016:9049 8016:90508016:9051 8016:9052 8016:9053 8000:9054 8000:9055 8000:9056 8000:90578000:9058 8000:9059 8001:9054 8001:9055 8001:9056 8001:9057 8001:90588001:9059 8002:9054 8002:9055 8002:9056 8002:9057 8002:9058 8002:90598003:9054 8003:9055 8003:9056 8003:9057 8003:9058 8003:9059 8004:90548004:9055 8004:9056 8004:9057 8004:9058 8004:9059 8005:9054 8005:90558005:9056 8005:9057 8005:9058 8005:9059 8006:9054 8006:9055 8006:90568006:9057 8006:9058 8006:9059 8007:9054 8007:9055 8007:9056 8007:90578007:9058 8007:9059 8008:9054 8008:9055 8008:9056 8008:9057 8008:90588008:9059 8009:9054 8009:9055 8009:9056 8009:9057 8009:9058 8009:90598010:9054 8010:9055 8010:9056 8010:9057 8010:9058 8010:9059 8011:90548011:9055 8011:9056 8011:9057 8011:9058 8011:9059 8012:9054 8012:90558012:9056 8012:9057 8012:9058 8012:9059 8013:9054 8013:9055 8013:90568013:9057 8013:9058 8013:9059 8014:9054 8014:9055 8014:9056 8014:90578014:9058 8014:9059 8015:9054 8015:9055 8015:9056 8015:9057 8015:90588015:9059 8016:9054 8016:9055 8016:9056 8016:9057 8016:9058 8016:90598000:9060 8000:9061 8000:9062 8000:9063 8000:9064 8000:9065 8001:90608001:9061 8001:9062 8001:9063 8001:9064 8001:9065 8002:9060 8002:90618002:9062 8002:9063 8002:9064 8002:9065 8003:9060 8003:9061 8003:90628003:9063 8003:9064 8003:9065 8004:9060 8004:9061 8004:9062 8004:90638004:9064 8004:9065 8005:9060 8005:9061 8005:9062 8005:9063 8005:90648005:9065 8006:9060 8006:9061 8006:9062 8006:9063 8006:9064 8006:90658007:9060 8007:9061 8007:9062 8007:9063 8007:9064 8007:9065 8008:90608008:9061 8008:9062 8008:9063 8008:9064 8008:9065 8009:9060 8009:90618009:9062 8009:9063 8009:9064 8009:9065 8010:9060 8010:9061 8010:90628010:9063 8010:9064 8010:9065 8011:9060 8011:9061 8011:9062 8011:90638011:9064 8011:9065 8012:9060 8012:9061 8012:9062 8012:9063 8012:90648012:9065 8013:9060 8013:9061 8013:9062 8013:9063 8013:9064 8013:90658014:9060 8014:9061 8014:9062 8014:9063 8014:9064 8014:9065 8015:90608015:9061 8015:9062 8015:9063 8015:9064 8015:9065 8016:9060 8016:90618016:9062 8016:9063 8016:9064 8016:9065 8000:9066 8000:9067 8000:90688000:9069 8000:9070 8000:9071 8001:9066 8001:9067 8001:9068 8001:90698001:9070 8001:9071 8002:9066 8002:9067 8002:9068 8002:9069 8002:90708002:9071 8003:9066 8003:9067 8003:9068 8003:9069 8003:9070 8003:90718004:9066 8004:9067 8004:9068 8004:9069 8004:9070 8004:9071 8005:90668005:9067 8005:9068 8005:9069 8005:9070 8005:9071 8006:9066 8006:90678006:9068 8006:9069 8006:9070 8006:9071 8007:9066 8007:9067 8007:90688007:9069 8007:9070 8007:9071 8008:9066 8008:9067 8008:9068 8008:90698008:9070 8008:9071 8009:9066 8009:9067 8009:9068 8009:9069 8009:90708009:9071 8010:9066 8010:9067 8010:9068 8010:9069 8010:9070 8010:90718011:9066 8011:9067 8011:9068 8011:9069 8011:9070 8011:9071 8012:90668012:9067 8012:9068 8012:9069 8012:9070 8012:9071 8013:9066 8013:90678013:9068 8013:9069 8013:9070 8013:9071 8014:9066 8014:9067 8014:90688014:9069 8014:9070 8014:9071 8015:9066 8015:9067 8015:9068 8015:90698015:9070 8015:9071 8016:9066 8016:9067 8016:9068 8016:9069 8016:90708016:9071 8000:9072 8000:9073 8000:9074 8000:9075 8000:9076 8000:90778001:9072 8001:9073 8001:9074 8001:9075 8001:9076 8001:9077 8002:90728002:9073 8002:9074 8002:9075 8002:9076 8002:9077 8003:9072 8003:90738003:9074 8003:9075 8003:9076 8003:9077 8004:9072 8004:9073 8004:90748004:9075 8004:9076 8004:9077 8005:9072 8005:9073 8005:9074 8005:90758005:9076 8005:9077 8006:9072 8006:9073 8006:9074 8006:9075 8006:90768006:9077 8007:9072 8007:9073 8007:9074 8007:9075 8007:9076 8007:90778008:9072 8008:9073 8008:9074 8008:9075 8008:9076 8008:9077 8009:90728009:9073 8009:9074 8009:9075 8009:9076 8009:9077 8010:9072 8010:90738010:9074 8010:9075 8010:9076 8010:9077 8011:9072 8011:9073 8011:90748011:9075 8011:9076 8011:9077 8012:9072 8012:9073 8012:9074 8012:90758012:9076 8012:9077 8013:9072 8013:9073 8013:9074 8013:9075 8013:90768013:9077 8014:9072 8014:9073 8014:9074 8014:9075 8014:9076 8014:90778015:9072 8015:9073 8015:9074 8015:9075 8015:9076 8015:9077 8016:90728016:9073 8016:9074 8016:9075 8016:9076 8016:9077 8000:9078 8000:90798000:9080 8000:9081 8000:9082 8000:9083 8001:9078 8001:9079 8001:90808001:9081 8001:9082 8001:9083 8002:9078 8002:9079 8002:9080 8002:90818002:9082 8002:9083 8003:9078 8003:9079 8003:9080 8003:9081 8003:90828003:9083 8004:9078 8004:9079 8004:9080 8004:9081 8004:9082 8004:90838005:9078 8005:9079 8005:9080 8005:9081 8005:9082 8005:9083 8006:90788006:9079 8006:9080 8006:9081 8006:9082 8006:9083 8007:9078 8007:90798007:9080 8007:9081 8007:9082 8007:9083 8008:9078 8008:9079 8008:90808008:9081 8008:9082 8008:9083 8009:9078 8009:9079 8009:9080 8009:90818009:9082 8009:9083 8010:9078 8010:9079 8010:9080 8010:9081 8010:90828010:9083 8011:9078 8011:9079 8011:9080 8011:9081 8011:9082 8011:90838012:9078 8012:9079 8012:9080 8012:9081 8012:9082 8012:9083 8013:90788013:9079 8013:9080 8013:9081 8013:9082 8013:9083 8014:9078 8014:90798014:9080 8014:9081 8014:9082 8014:9083 8015:9078 8015:9079 8015:90808015:9081 8015:9082 8015:9083 8016:9078 8016:9079 8016:9080 8016:90818016:9082 8016:9083 8000:9084 8000:9085 8000:9086 8000:9087 8000:90888000:9089 8001:9084 8001:9085 8001:9086 8001:9087 8001:9088 8001:90898002:9084 8002:9085 8002:9086 8002:9087 8002:9088 8002:9089 8003:90848003:9085 8003:9086 8003:9087 8003:9088 8003:9089 8004:9084 8004:90858004:9086 8004:9087 8004:9088 8004:9089 8005:9084 8005:9085 8005:90868005:9087 8005:9088 8005:9089 8006:9084 8006:9085 8006:9086 8006:90878006:9088 8006:9089 8007:9084 8007:9085 8007:9086 8007:9087 8007:90888007:9089 8008:9084 8008:9085 8008:9086 8008:9087 8008:9088 8008:90898009:9084 8009:9085 8009:9086 8009:9087 8009:9088 8009:9089 8010:90848010:9085 8010:9086 8010:9087 8010:9088 8010:9089 8011:9084 8011:90858011:9086 8011:9087 8011:9088 8011:9089 8012:9084 8012:9085 8012:90868012:9087 8012:9088 8012:9089 8013:9084 8013:9085 8013:9086 8013:90878013:9088 8013:9089 8014:9084 8014:9085 8014:9086 8014:9087 8014:90888014:9089 8015:9084 8015:9085 8015:9086 8015:9087 8015:9088 8015:90898016:9084 8016:9085 8016:9086 8016:9087 8016:9088 8016:9089 8000:90908000:9091 8000:9092 8000:9093 8000:9094 8000:9095 8001:9090 8001:90918001:9092 8001:9093 8001:9094 8001:9095 8002:9090 8002:9091 8002:90928002:9093 8002:9094 8002:9095 8003:9090 8003:9091 8003:9092 8003:90938003:9094 8003:9095 8004:9090 8004:9091 8004:9092 8004:9093 8004:90948004:9095 8005:9090 8005:9091 8005:9092 8005:9093 8005:9094 8005:90958006:9090 8006:9091 8006:9092 8006:9093 8006:9094 8006:9095 8007:90908007:9091 8007:9092 8007:9093 8007:9094 8007:9095 8008:9090 8008:90918008:9092 8008:9093 8008:9094 8008:9095 8009:9090 8009:9091 8009:90928009:9093 8009:9094 8009:9095 8010:9090 8010:9091 8010:9092 8010:90938010:9094 8010:9095 8011:9090 8011:9091 8011:9092 8011:9093 8011:90948011:9095 8012:9090 8012:9091 8012:9092 8012:9093 8012:9094 8012:90958013:9090 8013:9091 8013:9092 8013:9093 8013:9094 8013:9095 8014:90908014:9091 8014:9092 8014:9093 8014:9094 8014:9095 8015:9090 8015:90918015:9092 8015:9093 8015:9094 8015:9095 8016:9090 8016:9091 8016:90928016:9093 8016:9094 8016:9095 8000:9096 8000:9097 8000:9098 8000:90998000:9100 8000:9101 8001:9096 8001:9097 8001:9098 8001:9099 8001:91008001:9101 8002:9096 8002:9097 8002:9098 8002:9099 8002:9100 8002:91018003:9096 8003:9097 8003:9098 8003:9099 8003:9100 8003:9101 8004:90968004:9097 8004:9098 8004:9099 8004:9100 8004:9101 8005:9096 8005:90978005:9098 8005:9099 8005:9100 8005:9101 8006:9096 8006:9097 8006:90988006:9099 8006:9100 8006:9101 8007:9096 8007:9097 8007:9098 8007:90998007:9100 8007:9101 8008:9096 8008:9097 8008:9098 8008:9099 8008:91008008:9101 8009:9096 8009:9097 8009:9098 8009:9099 8009:9100 8009:91018010:9096 8010:9097 8010:9098 8010:9099 8010:9100 8010:9101 8011:90968011:9097 8011:9098 8011:9099 8011:9100 8011:9101 8012:9096 8012:90978012:9098 8012:9099 8012:9100 8012:9101 8013:9096 8013:9097 8013:90988013:9099 8013:9100 8013:9101 8014:9096 8014:9097 8014:9098 8014:90998014:9100 8014:9101 8015:9096 8015:9097 8015:9098 8015:9099 8015:91008015:9101 8016:9096 8016:9097 8016:9098 8016:9099 8016:9100 8016:91018000:9102 8000:9103 8000:9104 8000:9105 — — 8001:9102 8001:91038001:9104 8001:9105 8002:9102 8002:9103 8002:9104 8002:9105 8003:91028003:9103 8003:9104 8003:9105 8004:9102 8004:9103 8004:9104 8004:91058005:9102 8005:9103 8005:9104 8005:9105 8006:9102 8006:9103 8006:91048006:9105 8007:9102 8007:9103 8007:9104 8007:9105 8008:9102 8008:91038008:9104 8008:9105 8009:9102 8009:9103 8009:9104 8009:9105 8010:91028010:9103 8010:9104 8010:9105 8011:9102 8011:9103 8011:9104 8011:91058012:9102 8012:9103 8012:9104 8012:9105 8013:9102 8013:9103 8013:91048013:9105 8014:9102 8014:9103 8014:9104 8014:9105 8015:9102 8015:91038015:9104 8015:9105 8016:9102 8016:9103 8016:9104 8016:9105

EXAMPLES

Additional embodiments are disclosed in further detail in the followingexamples, which are not in any way intended to limit the scope of theclaims.

Example 1

To a stirred suspension of 1-1 (20 g, 77.5 mmol), PPh₃ (30 g, 114.5mmol), imidazole (10 g, 147 mmol) and pyridine (90 mL) in anhydrous THF(300 mL) was added a solution of I₂ (25 g, 98.4 mmol) in THF (100 mL)dropwise at 0° C. The mixture was warmed to room temperature (R.T.) andstirred at R.T. for 10 h. The reaction was quenched by MeOH (100 mL).The solvent was removed, and the residue was re-dissolved in a mixtureethyl acetate (EA) and THF (2 L, 10:1). The organic phase was washedwith saturated Na₂S₂O₃ aq., and the aqueous phase was extracted with amixture of EA and THF (2 L, 10:1). The organic layer was combined andconcentrated to give a residue, which was purified on a silica gelcolumn (0-10% MeOH in DCM) to give 1-2 (22.5 g, 78.9%) as a white solid.¹H NMR: (DMSO-d₆, 400 MHz) δ 11.42 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 5.82(s, 1H), 5.63 (d, J=8.0 Hz, 1H), 5.50 (s, 1H), 5.23 (s, 1H), 3.77-3.79(m, 1H), 3.40-3.62 (m, 3H), 0.97 (s, 3H).

To a stirred solution of 1-2 (24.3 g, 66.03 mmol) in anhydrous MeOH (240mL) was added NaOMe (10.69 g, 198.09 mmol) at R.T. under N₂. The mixturewas refluxed for 3 h. The solvent was removed, and the residue wasre-dissolved in anhydrous pyridine (200 mL). To the mixture was addedAc₂O (84.9 g, 833.3 mmol) at 0° C. The mixture was warmed to 60° C. andstirred for 10 h. The solvent was removed, and the residue was dilutedwith DCM, washed with saturated NaHCO₃ and brine. The organic layer wasconcentrated and purified on a silica gel column (10-50% EA in PE) togive 1-3 (15 g, 70.1%) as a white solid. ¹H NMR: (CDCl₃, 400 MHz) δ 8.82(s, 1H), 7.23 (d, J=2.0 Hz, 1H), 6.54 (s, 1H), 5.85 (s, 1H), 5.77 (dd,J=8.0, 2.0 Hz, 1H), 4.69 (d, J=2.4 Hz, 1H), 4.58 (d, J=2.8 Hz, 1H), 2.07(d, J=5.2 Hz, 6H), 1.45 (s, 3H).

To an ice-cooled solution of 1-3 (15 g, 46.29 mmol) in anhydrous DCM(300 mL) was added AgF (29.39 g, 231.4 mmol). I₂ (23.51 g, 92.58 mmol)in anhydrous DCM (1.0 L) was added dropwise to the solution. Thereaction mixture was stirred at R.T. for 5 h. The reaction was quenchedwith saturated Na₂S₂O₃ and NaHCO₃, and extracted with DCM. The organiclayer was separated, dried and evaporated to dryness. The residue waspurified on a silica gel column (10-30% EA in PE) to give 1-4 (9.5 g,43.6%) as a white solid. ¹H NMR: (Methanol-d₄, 400 MHz) δ 7.52 (d, J=8.0Hz, 1H), 6.21 (s, 1H), 5.80 (d, J=17.2 Hz, 1H), 5.73 (d, J=8.0 Hz, 1H),3.58 (s, 1H), 3.54 (d, J=6.8 Hz, 1H), 2.17 (s, 3H), 2.09 (s, 3H), 1.58(s, 3H).

To a solution of 1-4 (7.0 g, 14.89 mmol) in anhydrous DMF (400 mL) wereadded NaOBz (21.44 g, 148.9 mmol) and 15-crown-5 (32.75 g, 148.9 mmol).The reaction mixture was stirred at 130° C. for 6 h. The solvent wasremoved, diluted with EA and washed with water and brine. The organiclayer was evaporated and purified on a silica gel column (10-30% EA inPE) to give 1-5 (2.8 g, 40.5%). ¹H NMR: (CDCl₃, 400 MHz) δ 8.84 (s, 1H),8.04-8.06 (m, 2H), 7.59 (t, J=7.2 Hz, 1H), 7.44-7.47 (m, 2H), 7.21-7.26(m, 1H), 6.21 (s, 1H), 5.85 (d, J=18 Hz, 1H), 5.67 (d, J=8.0 Hz, 1H),4.59-4.72 (m, 2H), 2.14 (s, 6H), 1.64 (d, J=6.0 Hz, 3H). ESI-MS: m/z444.9 [M−F+H]⁺.

A mixture of 1-5 (4.0 g; 8.6 mmol) and liquid ammonia was kept overnightat R. T. in a high-pressure stainless-steel vessel. Ammonia was thenevaporated, and the residue purified on silica (50 g column) with aCH₂Cl₂/MeOH solvent mixture (4-12% gradient) to yield compound 1 as acolorless foam (2.0 g; 84% yield). ESI-MS: m/z 275.1 [M−H]⁻.

Example 2

To a solution of 1 (1.2 g; 4.3 mmol) in dioxane (30 mL) were addedp-toluenesulphonic acid monohydrate (820 mg; 1 eq.) and trimethylorthoformate (14 mL; 30 eq.). The mixture was stirred overnight at R.T.The mixture was then neutralized with methanolic ammonia and the solventevaporated. Purification on silica gel column with CH₂Cl₂-MeOH solventsystem (4-10% gradient) yielded 2-1 (1.18 g, 87%).

To an ice cold solution of 2-1 (0.91 g; 2.9 mmol) in anhydrous THF (20mL) was added iso-propylmagnesium chloride (2.1 mL; 2 M in THF). Themixture was stirred at 0° C. for 20 mins. A solution ofphosphorochloridate reagent (2.2 g; 2.5 eq.) in THF (2 mL) was addeddropwise. The mixture was stirred overnight at R.T. The reaction wasquenched with saturated aq. NH₄Cl solution and stirred at R.T. for 10mins. The mixture was then diluted with water and CH₂Cl₂, and the twolayers were separated. The organic layer was washed with water, halfsaturated aq. NaHCO₃ and brine, and dried with Na₂SO₄. The evaporatedresidue was purified on silica gel column with CH₂Cl₂-iPrOH solventsystem (4-10% gradient) to yield Rp/Sp-mixture of 2-2 (1.59 g; 93%).

A mixture of 2-2 (1.45 g; 2.45 mmol) and 80% aq. HCOOH (7 mL) wasstirred at R.T. for 1.5 h. The solvent was evaporated and coevaporatedwith toluene. The obtained residue was dissolved in MeOH, treated withEt₃N (3 drops) and the solvent was evaporated. Purification on silicagel column with CH₂Cl₂-MeOH solvent system (4-10% gradient) yieldedRp/Sp-mixture of compound 2 (950 mg; 70%). ³¹P-NMR (DMSO-d₆): δ 3.52,3.47. MS: m/z=544 [M−1]⁻.

Example 3

To an ice cold solution of 3-1 (80 mg; 015 mmol) in anhydrous THF (2 mL)was added isopropylmagnesium chloride (0.22 mL; 2 M in THF). The mixturewas stirred at 0° C. for 20 mins. A solution of the phosphorochloridatereagent (0.16 g; 0.45 mmol) in THF (0.5 mL) was added dropwise. Themixture was stirred overnight at R.T. The reaction was quenched withsaturated aq. NH₄Cl solution and stirred at R.T. for 10 mins. Themixture was diluted with water and CH₂Cl₂, and the two layers wereseparated. The organic layer was washed with water, half saturated aq.NaHCO₃ and brine, and dried with Na₂SO₄. The evaporated residue waspurified on silica gel column with CH₂Cl₂-MeOH solvent system (2-10%gradient) to yield Rp/Sp-mixture of 3-2 (102 mg; 80%).

A mixture of 3-2 (100 mg; 0.12 mmol) in EtOH (3 mL) and 10% Pd/C (10 mg)was stirred under the H₂ atmosphere for 1.5 h. The mixture was filteredthrough a Celite pad, evaporated and purified on silica gel column withCH₂Cl₂-MeOH solvent system (4-10% gradient) to yield Rp/Sp-mixture ofcompound 3 (52 mg, 74%). ³¹P-NMR (DMSO-d₆): δ 3.51, 3.48. MS: m/z=584[M−1]⁻.

Example 4

Dry 1 (14 mg, 0.05 mmol) was dissolved in the mixture of PO(OMe)₃ (0.750mL) and pyridine (0.5 mL). The mixture was evaporated in vacuum for 15mins at bath temperature 42° C., and then cooled down to R.T.N-Methylimidazole (0.009 mL, 0.11 mmol) was added followed by POCl₃(0.009 mL, 0.1 mmol). The mixture was kept at R.T. for 45 mins.Tributylamine (0.065 mL, 0.3 mmol) and N-tetrabutyl ammonium salt ofpyrophosphate (100 mg) was added. About 1 mL of dry DMF was added to geta homogeneous solution. In 1 h, the reaction was quenched with 2Mammonium acetate buffer (1 mL, pH=7.5), diluted water (10 mL) and loadedon a column HiLoad 16/10 with Q Sepharose High Performance. Theseparation was done in linear gradient of NaCl from 0 to 1N in 50 mMTRIS-buffer (pH7.5). The fractions eluted at 60% buffer B containedCompound 4 and at 80% buffer B contained Compound 6. The correspondingfractions were concentrated, and the residue purified by RP HPLC onSynergy 4 micron Hydro-RP column (Phenominex). A linear gradient ofmethanol from 0 to 30% in 50 mM triethylammonium acetate buffer (pH 7.5)was used for elution. The corresponding fractions were combined,concentrated and lyophilized 3 times to remove excess of buffer.Compound 4: ³¹P-NMR (D₂O): −3.76 (s); MS: m/z 355.3 [M−H]⁻. Compound 6:³¹P-NMR (D₂O): −9.28 (d, 1H, Pα), −12.31 (d, 1H, Pγ), −22.95 (t, 1H,Pβ); MS: m/z 515.0 [M−1]⁻.

Example 5

Compound 5 was synthesized as described for 2 on 0.1 mmol scale and withneopentyl ester of phosphorochloridate reagent. Yield was 36 mg (63%).³¹P-NMR (CDCl₃): δ 2.57 (s), 2.43 (s). MS: 572.6 [M−1]⁻.

Example 6

Dry 1 (14 mg, 0.05 mmol) was dissolved in the mixture of PO(OMe)₃ (0.750mL) and pyridine (0.5 mL). The mixture was evaporated in vacuum for 15mins at bath temperature 42° C., and then cooled down to R.T.N-Methylimidazole (0.009 mL, 0.11 mmol) was added followed by PSCl₃(0.01 mL, 0.1 mmol). The mixture was kept at R.T. for 1 h. Tributylamine(0.065 mL, 0.3 mmol) and N-tetrabutyl ammonium salt of pyrophosphate(200 mg) was added. About 1 mL of dry DMF was added to get a homogeneoussolution. In 2 h, the reaction was quenched with 2M ammonium acetatebuffer (1 mL, pH=7.5), diluted with water (10 mL) and loaded on a columnHiLoad 16/10 with Q Sepharose High Performance. Separation was done inlinear gradient of NaCl from 0 to 1N in 50 mM TRIS-buffer (pH7.5). Thefractions eluted at 80% buffer B contained 7 (compounds 7a and 7b). Thecorresponding fractions were concentrated, and the residue purified byRP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A lineargradient of methanol from 0 to 20% in 50 mM triethylammonium acetatebuffer (pH 7.5) was used for elution. Two peaks were collected. Thecorresponding fractions were combined, concentrated and lyophilized 3times to remove excess of buffer. Peak 1 (more polar): ³¹P-NMR (D₂O):+42.68 (d, 1H, Pα), −9.05 (d, 1H, Pγ), −22.95 (t, 1H, Pβ); MS 530.90[M−1]⁻. Peak 2 (less polar): ³¹P-NMR (D₂O): +42.78 (d, 1H, Pα), −10.12(bs, 1H, Pγ), −23.94 (t, 1H, Pβ); and MS 530.90 [M−1]⁻.

Example 7

To a stirred suspension of 23-1 (20.0 g, 81.3 mmol), imidazole (15.9 g,234.0 mmol), PPh₃ (53.5 g, 203.3 mmol) and pyridine (90 mL) in anhydrousTHF (100 mL) was added a solution of I₂ (41.3 g, 162.6 mmol) in THF (150mL) dropwise at 0° C. The mixture was slowly warmed to R.T. and stirredfor 14 h. The reaction was quenched with sat. aq. Na₂S₂O₃ (150 mL) andextracted with THF/EA (1/1) (100 mL×3). The organic layer was dried overNa₂SO₄, and concentrated at a low pressure. The residue wasrecrystallized from EtOH to afford pure 23-2 (23 g, 79%) as a whitesolid.

To a stirred solution of 23-2 (23 g, 65 mmol) in anhydrous MeOH (200 mL)was added NaOCH₃ (10.5 g, 195 mmol) in MeOH (50 mL) at R.T. The mixturewas stirred at 60° C. for 3 h, and quenched with dry ice. A solidprecipitated and removed by filtration. The filtrate was concentrated ata low pressure. The residue was purified on column silica gel column(MeOH in DCM from 1% to 10%) to provide 23-3 (13.1 g, 92.5%) as a whitefoam solid.

To a stirred solution of 23-3 (12.0 g, 53 mmol) in anhydrous CH₃CN wasadded TEA.3HF (8.5 g, 53 mmol) and NIS (10.2 g, 63.6 mmol) at 0° C. Themixture was stirred for 30 mins, and slowly warmed to R.T. The mixturewas stirred for another 30 mins. The solid was removed by filtration,and washed with DCM to give 23-4 (14 g, 73%) as a yellow solid. ESI-MS:m/z 373.0 [M+H]⁺.

To a stirred solution of 23-4 (12.0 g, 32 mmol) and DMAP (1.2 g, 9.6mmol) in pyridine (100 mL) was added Bz₂O (21.7 g, 96 mmol) at R.T. Themixture was stirred at 50° C. for 16 h. The resulting solution wasquenched with water, and concentrated to dryness at low pressure. Thecrude was purified on silica gel column (50% EA in PE) to give 23-5 (15g, 81%) as a white solid. ESI-TOF-MS: m/z 581.0 [M+H]⁺.

Tetra-butylammonium hydroxide (288 mL as 54-56% aqueous solution, 576mmol) was adjusted to pH˜4 by adding TFA (48 mL). The resulting solutionwas treated with a solution of 23-5 (14 g, 24 mmol) in DCM (200 mL).m-Cloroperbenzoic acid (30 g, 60-70%, 120 mmol) was added portion wisewith vigorous stirring, and the mixture was stirred overnight. Theorganic layer was separated and washed with brine. The resultingsolution was dried over magnesium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography to give 23-6(7.5 g, 68%)

Compound 23-6 (5.0 g, 10.6 mmol) was treated with 7N NH₃.MeOH (100 mL),and the mixture was stirred for 5 h. The mixture was then concentratedto dryness at low pressure. The residue was washed with DCM, and thesolid was filtered to give 23-7 (2.1 g, 75%) as a white foam. ESI-MS:m/z 263.0 [M+H]⁺.

To a solution of 23-7 (2.1 g, 8.0 mmol) in pyridine was added TIDPSCl(2.5 g, 8.0 mmol) dropwise at 0° C., and stirred for 12 h. at R.T. Thesolution was quenched with water, and concentrated to dryness at lowpressure. The crude was purified by column chromatography (EA in PE from10% to 50%) to give pure 23-8 (1.6 g, 40%) as a white foam.

A solution of 23-8 (1.5 g, 3.0 mmol) and IBX (1.69 g, 6.0 mmol) inanhydrous CH₃CN (10 mL) was stirred at 80° C. for 3 h. The mixture wascooled down to R.T. and filtered. The filtrate was concentrated todryness at low pressure. The residue was purified by columnchromatography (EA in PE from 2% to 50%) to give pure 23-9 (1.2 g, 80%)as a white foam. ESI-MS: m/z 503.0 [M+H]⁺

Compound 23-9 (500 mg, 1 mmol) was dissolved in dry THF (8 mL). Ethynylmagnesium bromide (8 mL of 0.5M solution in cyclohexane) was added atR.T. After 30 mins, additional ethynyl magnesium bromide (8 mL) wasadded. The mixture was left for 30 mins, and then quenched with sat.solution of ammonium chloride. The product was extracted with EA. Theorganic extracts were washed with brine, dried, and concentrated. Theresidue was purified by flash chromatography on silica gel in EA toremove the dark color. The yellow compound was dissolved in THF (3 mL)and treated with TBAF (1 mL, 2M solution in THF) for 30 mins. Thesolvent was evaporated, and the residue was subjected to silica gelchromatography on a Biotage cartridge (25 g). EA saturated with waterwas used for isocratic elution. Each fractions were analyzed by TLC inDCM-MeOH (9:1 v/v). Fractions containing only the isomer with a high Rfwere concentrated to give pure compound 23 (110 mg). MS: 285.1 [M−1]⁻.

Example 8

Compound 23 (57 mg, 0.2 mmol) was dissolved in CH₃CN (2 mL), containingN-methylimidazole (40 uL). The phosphorochloridate (207 mg, 0.6 mmol)was added, and the mixture was kept overnight at 40° C. The mixture wasdistributed between water and EA. The organic layer was separated,washed with brine, dried and evaporated. The product was isolated bysilica gel chromatography in gradient of methanol in DCM from 0% to 15%.Compound 22 was obtained (46 mg, 39%). MS: m/z 593.9 [M−1]⁻.

Example 9

To a solution of triethylammoniumbis(isopropyloxycarbonyloxymethyl)phosphate (0.74 mmol) in THF was added51-1 (0.16 gg; 0.49 mmol). The mixture evaporated and rendered anhydrousby coevaporating with pyridine follow by toluene. The residue wasdissolved in anhydrous THF and cooled in an ice-bath. Diisopropylethylamine (0.34 mL) was added, followed by BOP—Cl (250 mg) and3-nitro-1,2,4-triazole (112 mg) in THF (5 mL). The mixture was stirredat 0° C. for 90 mins, diluted with EtOAc, washed with sat. aq. NaHCO₃and brine, and dried (Na₂SO₄). The residue was purified on silica columnwith 3-10% i-PrOH in DCM to give 51-2 (0.2 g, 64%).

A solution of 51-2 (0.20 g; 0.31 mmol) in 80% aq. HCOOH was stirred atR.T. for 2 h, and then concentrated. The residue was coevaporated withtoluene and then with MeOH containing a small amount of Et₃N (2 drops).Purification on silica gel (10 g column) with CH₂Cl₂/MeOH (4-10%gradient) was followed by RP-HPLC purification in 5 runs on a SynergiHydro RP column 250×30 mm (Phenomenex P/N 00G-4375-U0-AX) using H₂O andACN both 50 mM TEAA. The Gradient was 25-75% ACN in 20 mins at 24mL/mins, 254 nM detection. The compound eluted at 16.0 minutes; and thepure fractions were pooled and lyophilized. TEAA was removed bydissolving the compound in DMSO (2 mL) and using the same column andsame gradient, using only H₂O and ACN. Pure fractions were pooled andlyophilized to give compound 51 (18 mg). MS: m/z=1197 [2M+1]⁺.

Example 10

Compound 8-1 (5.0 g, 8.5 mmol) and 2-amino-6-chloropurine (3.0 g, 17.7mmol) were co-concentrated with anhydrous toluene for 3 times. To astirred suspension of the above mixtures in anhydrous MeCN (50 mL) wasadded DBU (7.5 g, 49 mmol) at 0° C. The mixture was stirred at 0° C. for15 mins, and then TMSOTf (15 g, 67.6 mmol) was added dropwise at 0° C.The mixture was stirred at 0° C. for 15 mins. The mixture was heated at70° C. overnight. The mixture was cooled to R.T., and diluted with EA(100 mL). The solution was washed with sat. NaHCO₃ solution and brine.The organic layer was dried over Na₂SO₄ and concentrated at lowpressure. The residue was purified by column on silica gel (PE/EA: from15/1 to 3/1) to give 8-2 (2.5 g, 46.3%) as a white foam.

To a solution of 8-2 (10 g, 15.7 mmol), AgNO₃ (8.0 g, 47 mmol) andcollidine (10 mL) in anhydrous DCM (20 mL) was added MMTrCl (14.5 g, 47mmol) in small portions under N₂. The mixture was stirred at R.T.overnight. The mixture was filtered, and the filtrate was washed withsat. aq. NaHCO₃ and brine. The organic layer was dried over anhydrousNa₂SO₄, and concentrated at low pressure. The residue was purified bysilica gel column (PE/ME=20/1 to 8/1) to give 8-3 (10 g, 70%) as ayellow solid.

To a solution of 3-hydroxy-propionitrile (3.51 g, 49.4 mmol) inanhydrous THF (100 mL) was added NaH (2.8 g, 70 mmol) at 0° C., and themixture was stirred at R.T. for 30 mins. A solution of 8-3 (8.5 g, 9.35mmol) in anhydrous THF (100 mL) at 0° C. was added, and the mixture wasstirred at R.T. overnight. The reaction was quenched with water, andextracted with EA (100 mL). The organic layer was dried over anhydrousNa₂SO₄, and concentrated at low pressure. The residue was purified bysilica gel column (DCM/MeOH=100/1 to 20/1) to give 8-4 (4.5 g, 83%) as awhite solid.

Compound 8-4 (1.5 g, 2.6 mmol) was co-concentrated with anhydrouspyridine 3 times. To an ice-cooled solution of 8-4 in anhydrous pyridine(30 mL) was added TsCl (1.086 g, 5.7 mmol), and the mixture was stirredat 0° C. for 1 h. The reaction was quenched with water, and extractedwith EA (80 mL). The organic layer was dried over anhydrous Na₂SO₄, andconcentrated at low pressure. The residue was purified by silica gelcolumn (DCM/MeOH=100/1 to 15/1) to give 8-5 (1.4 g, 73%) as a whitesolid.

To a solution of 8-5 (4.22 g, 5.7 mmol) in acetone (60 mL) was added NaI(3.45 g, 23 mmol), and the mixture was refluxed overnight. The reactionwas quenched with sat. aq. Na₂S₂O₃ and extracted with EA (100 mL). Theorganic layer was dried over anhydrous Na₂SO₄, and concentrated at lowpressure. The residue was purified by silica gel column (DCM/MeOH=100/1to 15/1) to give 8-6 (4 g, 73%) as a white solid.

To a solution of 8-6 (4.0 g, 5.8 mmol) in anhydrous THF (60 mL) wasadded DBU (3.67 g, 24 mmol), and the mixture was stirred at 60° C.overnight. The mixture was diluted with EA (80 mL), and the solution waswashed with brine. The organic layer was dried over anhydrous Na₂SO₄,and concentrated at low pressure. The residue was purified by silica gelcolumn (DCM/MeOH=100/1 to 20/1) to give 8-7 (2 g, 61%) as a white solid.

To an ice-cooled solution of 8-7 (500 mg, 0.89 mmol) in anhydrous DCM(20 mL) was added AgF (618 mg, 4.9 mmol) and a solution of I₂ (500 mg,1.97 mmol) in anhydrous DCM (20 mL). The mixture was stirred at R.T. for3 h. The reaction was quenched with sat Na₂S₂O₃ and NaHCO₃ aqueous, andthe mixture was extracted with DCM (50 mL). The organic layer wasseparated, dried over anhydrous Na₂SO₄, and concentrated to give thecrude 8-8 (250 mg) as a yellow solid.

To a solution of crude 8-8 (900 mg, 1.28 mmol) in anhydrous DCM (50 mL)was added DMAP (1.0 g, 8.2 mmol) and BzCl (795 mg, 5.66 mmol). Themixture was stirred at R.T. overnight. The mixture was washed with sat.aq. NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄,and concentrated at low pressure. The residue was purified by prep-TLC(DCM/MeOH=15:1) to give 8-9 (300 mg, 26%) as a white solid.

To a solution of crude 8-9 (750 mg, 0.82 mmol) in anhydrous HMPA (20 mL)was added NaOBz (1.2 g, 8.3 mmol) and 15-crown-5 (1.8 g, 8.3 mmol). Themixture was stirred at 60° C. for 2 d. The mixture was diluted with EA,and the solution was washed with brine. The organic layer was dried overanhydrous Na₂SO₄, and concentrated at low pressure. The residue waspurified by prep-TLC (PE/EA=1:1) to give crude 8-10 (550 mg, 73%) as awhite solid.

The crude 8-10 (550 mg, 0.6 mmol) was dissolved in NH₃/MeOH (7N, 50 mL).The mixture was stirred at R.T. overnight. The mixture was concentrated,and the residue was purified by silica gel column (DCM/MeOH from 100/1to 20/1) to give 8-11 (62 mg, 17%) as a white solid. ESI-MS: m/z 598.0[M+H]⁺

A solution of 8-11 (12 mg) in 80% formic acid (0.5 mL) stood at R.T. for3.5 h and then was concentrated. The residue was co-evaporated withMeOH/toluene 4 times in a vial, and triturated with EtOAc at 40° C. TheEtOAc solution removed with pippet. The trituration step was repeatedseveral times, and the remaining solid was dissolved in MeOH. Thesolution was concentrated and dried to give compound 8 as off whitesolid (4.7 mg). ESI-MS: m/z 326.6 [M+H]⁺.

Example 11

To a stirred suspension of 8-1 (50 g, 84.8 mmol) and2-amino-6-chloropurine (28.6 g, 169.2 mmol) in anhydrous MeCN (500 mL)was added DBU (77.8 g, 508 mmol) at 0° C. The mixture was stirred at 0°C. for 30 mins, and TMSOTf (150.5 g, 678 mmol) was added dropwise at 0°C. The mixture was stirred at R.T. for 20 mins until a clear solutionwas formed. The mixture was stirred at 90-110° C. overnight. The mixturewas cooled to R.T., and diluted with EA. The solution was washed withsat. NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄and then concentrated at low pressure. The residue was purified bysilica gel column (PE/EA=2/1) to give 34-1 (30 g, 55.5%) as a whitesolid.

To a solution of 34-1 (30 g, 47.1 mmol) in anhydrous DCM (300 mL) wasadded collidine (30 mL), AgNO₃ (24 g, 141.4 mmol) and MMTrCl (43.6 g,141.4 mmol). The mixture was stirred at R.T. overnight. The mixture wasfiltered, and the filtrate was washed with water and brine. The organiclayer was dried over anhydrous Na₂SO₄, and concentrated at low pressure.The residue was purified by silica gel column (PE/EA=4/1) to give 34-2(35 g, 82%) as a white solid.

To a stirred solution of 34-2 (35 g, 38.5 mmol) in anhydrous EtOH (150mL) was added a solution of EtONa in EtOH (2N, 150 mL). The mixture wasstirred at R.T. overnight, and then concentrated at low pressure. Theresidue was dissolved in EA (200 mL) and the solution was washed withwater and brine. The organic layer was dried over Na₂SO₄, andconcentrated at low pressure. The residue was purified by silica gelcolumn (DCM/MeOH=100/2) to give 34-3 (19 g, 81%) as a white solid.

Compound 34-3 (19 g, 31.3 mmol) was co-concentrated with anhydrouspyridine for 3 times. To an ice-cooled solution of 34-3 in anhydrouspyridine (120 mL) was added a solution of TsCl (6.6 g, 34.6 mmol) inpyridine (40 mL) dropwise at 0° C. The mixture was stirred at 0° C. for16 h. The mixture was quenched with water, and the reaction mixture wasconcentrated. The residue was re-dissolved in EA (200 mL). The solutionwas washed with sat. aq. NaHCO₃ and brine. The organic layer was driedover anhydrous Na₂SO₄ and filtered, and the filtrate was concentrated.The residue was purified by silica gel column (DCM/MeOH=100/1) to give34-4 (16 g, 67%) as a yellow solid.

To a solution of 34-4 (15 g, 19.7 mmol) in acetone (100 mL) was addedNaI (30 g, 197 mmol). The mixture was refluxed overnight, and thenconcentrated at low pressure. The residue was purified by silica gelcolumn (DCM/MeOH=100/1) to give 34-5 (9 g, 63.7%) as a white solid.

To a solution of 34-5 (8 g, 11.2 mmol) in anhydrous THF (60 mL) wasadded DBU (5.12 g, 33.5 mmol), and the mixture was heated at 60° C.overnight. The mixture was diluted with EA, and washed with water andbrine. The organic layer was dried over anhydrous Na₂SO₄ and filtered,and the filtrate was concentrated. The residue was purified by silicagel column (PE/acetone=4/1) to give 34-6 (5.7 g, 86%) as a white solid.¹H-NMR (CD₃OH, 400 MHz) δ=8.18 (s, 1H), 7.17-7.33 (m, 12H), 6.80 (d,J=8.8 Hz, 2H), 5.98 (s, 1H), 5.40 (d, J=8.6 Hz, 1H), 3.87 (m, 5H), 3.75(s, 3H), 2.69 (s, 1H), 1.05 (s, 3H).

To an ice-cooled solution of 34-6 (4.44 g, 7.5 mmol) in anhydrous MeCN(45 mL) was added TEA.3HF (1.23 g, 7.6 mmol) and NIS (2.16 g, 9.5 mmol).The mixture was stirred at R.T. for 2-3 h. The reaction was quenchedwith sat. Na₂SO₃ and NaHCO₃ solution. The mixture was extracted with EA(3×100 mL). The organic layer was separated, dried over anhydrous Na₂SO₄and concentrated at low pressure. The residue was purified by silica gelcolumn (DCM/acetone=100/2) to give 34-7 (4.4 g, 79.8%) as a white solid.

To a solution of 34-7 (5.36 g, 7.3 mmol) in anhydrous DCM (50 mL) wasadded DMAP (3.6 g, 29.8 mmol) and BzCl (3.1 g, 22.1 mmol) at 0° C. Themixture was stirred at R.T. overnight. The mixture was washed with sat.aq. NaHCO₃ and brine. The organic layer was concentrated, and theresidue was purified by silica gel column (PE/EA=5/1) to give 34-8 (5.6g, 81.3%) as a white solid.

To a solution of 34-8 (5.0 g, 5.3 mmol) in anhydrous DMF (150 mL) wasadded NaOBz (7.64 g, 53 mmol) and 15-crown-5 (14 g, 68 mmol). Themixture was stirred at 90-100° C. for 48 h. The mixture was diluted withEA, and washed with water and brine. The organic layer was concentrated,and the residue was purified by silica gel column (PE/EA=5/1) to give34-9 (3.9 g, 78.5%) as a white solid.

Compound 34-9 in NH₃ in MeOH (7N, 60 mL) was stirred at R.T. for 18 h.The mixture was concentrated at low pressure. The residue was purifiedby silica gel column (DCM/acetone=50/1) to give 34-10 (500 mg, 74.7%) asa white solid. ESI-MS: m/z 626.3 [M+H]⁺.

To a solution of 34-10 (350 mg, 0.56 mmol) in anhydrous pyridine (4 mL)was added imidazole (50 mg, 0.72 mmol) and TBSCl (108 mg, 0.72 mmol) at0 to 5° C., and stirred at R.T. for 15 h. The reaction was quenched withabsolute EtOH (0.5 mL). The solution was concentrated to dryness underreduced pressure. The residue was dissolved in EA (150 mL), and washedwith water, sat. NaHCO₃ and brine. The combined organic layers weredried over Na₂SO₄, filtered and evaporated at low pressure. The residuewas purified by silica gel column (10-30% EA in hexanes) to give 34-11(338 mg, 81.8%) as a white solid.

To a solution of compound 34-11 (328 mg, 0.44 mmol), AgNO₃ (226 mg, 1.33mmol) and collidine (0.59 mL, 4.84 mmol) in anhydrous DCM (4 mL) wasadded MMTrCl (410 mg, 1.33 mmol) under N₂. The mixture was stirred atR.T. overnight under N₂, and monitored by TLC to completion. The mixturewas filtered through pre-packed Celite filter, and the filtrate waswashed with water, 50% aqueous citric acid, and brine. The organic layerwas separated, dried over anhydrous Na₂SO₄, filtered and concentrated atlow pressure. The residue was purified by silica gel column (EA inhexanes from 0% to 30%) to give 34-12 (337 mg).

To a solution of 34-12 (337 mg, 0.33 mmol) in anhydrous THF (4 mL) wasadded 1.0 M solution of TBAF (0.66 ML, 0.66 mmol) at 0 to 5° C. Thereaction was slowly warmed to R.T., and stirred for 1 h. The mixture wasquenched with silica gel, and filtered. The solvents were evaporated togive the crude product, which was purified by silica gel column (EA inhexanes from 0% to 50%) to give 34-13 (188 mg).

To a stirred solution of 34-13 (180 mg, 0.16 mmol) in anhydrous CH₃CN(2.5 mL) was added N-methylimidazole (132 μL, 1.6 mmol) at 0-5° C.(ice/water bath) followed by solution of phenyl(cyclohexanoxy-L-alaninyl)phosphorochloridate (207 mg, 0.6 mmol,dissolved in 2 mL of CH₃CN). The solution was stirred at R.T. for 2.5 h,and the mixture was diluted with EA followed by addition of water (15mL). The solution was washed H₂O, 50% aqueous citric acid solution andbrine. The organic layer was separated, dried over anhydrous MgSO₄ andfiltered. The filtrate was concentrated in vacuum to give a residue,which was purified on silica gel with 0 to 40% EA/hexanes to give 34-14(75.8 mg) and 34-15 (108 mg) as a slower eluting isomer.

Compound 34-14 (76 mg, 0.063 mmol) was dissolved in_anhydrous CH₃CN (0.5mL), and 4N HCl in dioxane (47 μL) was added at 0 to 5° C. (ice/waterbath). The mixture was stirred at R.T. for 40 mins, and anhydrous EtOH(200 μL) was added. The solvents were evaporated at R.T. andco-evaporated with toluene 3 times. The residue was dissolved in 50%CH₃CN/H₂O, purified on a reverse-phase HPLC (C18) using acetonitrile andwater, and lyophilized to give compound 34 (26.6 mg). ESI-LCMS:m/z=663.3 [M+H]⁺.

Compound 34-15 (108 mg, 0.089 mmol) was dissolved in_anhydrous CH₃CN(0.7 mL), and 4N HCl in dioxane (67 μL) was added at 0 to 5° C.(ice/water bath). The mixture was stirred at R.T. for 60 mins, andanhydrous EtOH (200 μL) was added. The solvents were evaporated at R.T.and co-evaporated with toluene 3 times. The residue was dissolved in 50%CH₃CN/H₂O, purified on a reverse-phase HPLC (C18) using acetonitrile andwater, and lyophilized to give compound 35 (40.3 mg). ESI-LCMS:m/z=663.2 [M+H]⁺.

Example 12

To a solution of 25-1 (260 mg, 1 mmol), PPh₃ (780 mg, 3 mmol) andpyridine (0.5 mL) in anhydrous THF (8 mL) were added I₂ (504 mg, 2 mmol)at R.T., and the mixture was stirred at R.T. for 12 h. The mixture wasdiluted with EtOAc and washed with 1M HCl solution. The organic layerwas dried over Na₂SO₄, filtered and concentrated at low pressure. Theresidue was purified by silica gel column (5% MeOH in DCM) to give 25-2(190 mg, 85%) as a white solid.

To a solution of 25-2 (190 mg, 0.52 mmol) in THF (4 mL) was added DBU(760 mg, 5 mmol) at R.T., and the mixture was heated at 50° C.overnight. The mixture was diluted with EtOAc, and washed with water.The organic layer was dried over anhydrous Na₂SO₄ and concentrated atlow pressure. The residue was purified by silica gel column (30% EA inPE) to give 25-3 (75 mg, 52%) as a white solid.

To a solution of 25-3 (200 mg, 0.82 mmol) in MeCN (anhydrous, 4 mL) wasadded NIS (337 mg, 1.5 mmol) and TEA.3HF (213 mg, 1.25 mmol) at R.T.,and the mixture was stirred at R.T. for 7 h. The reaction was quenchedwith sat. Na₂SO₃ solution and sat. aq. NaHCO₃ solution. The mixture wasextracted with EA. The organic layer was separated, dried over anhydrousNa₂SO₄, and concentrated at low pressure. The residue was purified bysilica gel column (20% EA in PE) to give 25-4 (300 mg, 62%) as a whitesolid.

To a solution of 25-4 (194 mg, 0.5 mmol) in pyridine (5 mL) was addedBzCl (92 mg, 0.55 mmol) at 0° C. The mixture was stirred at R.T. for 5h, and the reaction was quenched with water. The mixture wasconcentrated at low pressure, and the residue was purified by silica gelcolumn (20% EA in PE) to give 25-5 (397 mg, 81%) as a white solid.

To a solution of 25-5 (1.05 g, 2.13 mmol) in DCM (12 mL) was added amixture of TFA (0.5 mL) and Bu₄NOH (1 mL), followed by addition ofm-CPBA (1.3 g, 6 mmol) at R.T. The mixture was stirred at R.T. for 5 h.The mixture was washed with sat. Na₂SO₃ solution and aq. NaHCO₃solution. The organic layer was dried over anhydrous Na₂SO₄, andconcentrated at low pressure. The residue was purified by silica gelcolumn (30% EA in PE) to give 25-6 (450 mg, 63%) as a white solid.

Compound 25-6 (250 mg, 0.65 mmol) was dissolved in NH₃/MeOH (5 mL). Themixture was stirred at R.T. for 5 h, and then concentrated at lowpressure. The residue was purified by silica gel column (5% MeOH in DCM)to give compound 25 (120 mg, 66%) as a white powder. ESI-MS: m/z 279.0[M+H]⁺.

Example 13

To a stirred solution of compound 25 (100 mg, 0.36 mmol) in anhydrousTHF (3.0 mL) was added N-methylimidazole (236 μL, 2.87 mmol) at 0° C.(dry ice/acetone bath) followed by a solution of the phosphorochloridate(329 mg, 1.08 mmol, dissolved in 2 mL of THF). The solution was stirredat 0° C. for 1 h, the reaction temperature was raised up-to 10° C.during the next 1 h, and the solution was left at 10° C. for the next 4h. The mixture was cooled to 0 to 5° C., diluted with EA, and water wasadded (15 mL). The solution was washed H₂O, 50% aqueous citric acidsolution and brine. The organic layer was separated, dried overanhydrous MgSO₄ and filtered. The filtrate was concentrated in vacuum togive a residue, which dissolved in 25% CH₃CN/H₂O. The residue waspurified on a reverse-phase HPLC (C18) using acetonitrile and water,followed by lyophilization to give a mixture of two isomers of compound31 (17.5 mg). MS: m/z 546.05 [M−H]⁻.

Example 14

To a solution of compound 25 (139 mg, 0.5 mmol) in pyridine (5 mL) wasadded BzCl (92 mg, 0.55 mmol) at 0° C. The mixture was stirred at R.T.for 5 h, diluted with EtOAc and washed with 1N HCl solution. The organiclayer was dried over anhydrous Na₂SO₄, and concentrated at low pressure.The residue was purified by silica gel column (20% EA in PE) to give27-1 (274 mg, 79%) as a white solid.

To a solution of 27-1 (490 mg, 1 mmol), DMAP (244 mg, 2 mmol) and TEA(205 mg, 2.1 mmol) in MeCN (10 mL) were added TPSCl (604 mg, 2 mmol) at0° C. The mixture was stirred at R.T. for 2 h., and then NH₄OH aq. wasadded at R.T. The mixture was stirred for 0.5 h, diluted with EtOAc andwashed with sat. aq. NaHCO₃ and brine. The organic layer was dried overanhydrous Na₂SO₄, and concentrated at low pressure. The residue waspurified by silica gel column (30% EA in PE) to give 27-2 (250 mg, 41%)as a white solid.

Compound 27-2 (250 mg, 0.51 mmol) was dissolved in NH₃/MeOH (15 mL). Themixture was stirred at R.T. for 5 h. and then concentrated at lowpressure. The residue was purified by silica gel column (5% DCM in DCM)to give compound 27 (95 mg, 66%) as a white powder. ESI-MS: m/z 278.1[M+H]⁺.

Example 15

To a solution of compound 29-1 (30 g, 0.08 mol) in anhydrous THF (300mL) was added a solution of lithium tri-tert-butoxyaluminohydride (120mL, 0.12 mol) dropwise at −78° C. under N₂. The mixture was stirred at−20° C. for 1 h. The reaction was quenched with sat. aq. NH₄Cl and thenfiltered. The filtrate was extracted with EA (3×300 mL). The organiclayer was dried over anhydrous Na₂SO₄, and concentrated at low pressure.The residue was purified by silica gel column (10% EA in PE) to give29-2 (26 g, 86%) as a colorless oil.

To a stirred solution of PPh₃ (37.7 g, 0.144 mol) in DCM (100 mL) wasadded compound 29-2 (27 g, 0.072 mol) at −20° C. under N₂. After themixture was stirred at R.T. for 15 mins, CBr₄ (42 g, 0.129 mol) wasadded while maintaining the reaction temperature between −25 and −20° C.under N₂. The mixture was then stirred below −17° C. for 20 mins. Silicagel was added into the solution, and then purified by flash silica gelcolumn separation to give the crude oil product. The crude was purifiedby silica gel column (EA in PE from 2% to 20%) to give 29-3 (a-isomer,17 g, 55%) as a colorless oil.

A mixture of 6-Cl-guanine (11.6 g, 68.8 mmol) and t-BuOK (8.2 g, 73mmol) in t-BuOH (200 mL) and MeCN (150 mL) was stirred at 35° C. for 30mins, and then 29-3 (10 g, 22.9 mmol) in MeCN 100 mL) was added at R.T.The mixture was heated at 50° C. overnight. The reaction was quenchedwith a solution of NH₄Cl (5 g) in water (40 mL), and the mixture wasfiltered. The filtrate was evaporated at low pressure. The residue waspurified by silica gel column (20% EA in PE) to give 29-4 (6 g, 42%) asa yellow solid.

To a solution of 29-4 (12.5 g, 23.8 mol) in DCM (50 mL) was added AgNO₃(8.1 g, 47.6 mmol), collidine (5.77 g, 47.6 mmol) and MMTrCl (11 g, 35.7mmol). The mixture was stirred at R.T. overnight. The reaction wasquenched with MeOH (5 mL), filtered and concentrated at low pressure.The residue was purified by silica gel column (5% MeOH in DCM) to givethe intermediate (16 g, 86%) as a yellow solid. To a solution ofHOCH₂CH₂CN (4.7 g, 66 mmol) in THF (200 mL) was added NaH (3.7 g, 92mmol) at 0° C. The mixture was stirred at R.T. for 30 mins. A solutionof the intermediate (10.5 g, 13 mmol) in THF (50 mL) was added, and thereaction mixture was stirred at R.T. for 12 h. The reaction was quenchedwith MeOH (2 mL), diluted with EA (100 mL), and washed with brine. Theorganic layer was dried over anhydrous Na₂SO₄, and concentrated at lowpressure. The residue was purified by silica gel column (5% MeOH in DCM)to give 29-5 (5.8 g, 77%) as a yellow solid.

To a solution of PPh₃ (7.0 g, 26.6 mmol) in anhydrous pyridine (100 mL)was added I₂ (6.3 g, 24.9 mmol), and stirred at R.T. for 30 mins. Themixture was treated with a solution of 29-5 (9.5 g, 16.6 mmol) inpyridine (40 mL). The mixture was stirred at R.T. overnight. Thereaction was quenched with sat. Na₂S₂O₃ solution, and the mixture wasextracted with EA. The organic layer was washed with brine, dried overanhydrous Na₂SO₄, and concentrated at low pressure. The residue waspurified by silica gel column (30% EA in PE) to give 29-6 (7 g, 66%) asa yellow solid.

To a solution of 29-6 (7.5 g, 11 mmol) in dry THF (50 mL) was added DBU(5.4 g, 33 mmol), and the mixture was heated to reflux for 4 h. Themixture was diluted with EA (3×100 mL), and washed with brine. Theorganic layer was dried over anhydrous Na₂SO₄, and concentrated at lowpressure. The residue was purified by silica gel column (30% EA in PE)to give 29-7 (4.0 g, 67%) as a white solid.

To an ice-cooled solution of 29-7 (3.0 g, 5.4 mmol) in anhydrous MeCN(20 mL) was added TEA.3HF (0.65 g, 4.1 mmol) and NIS (1.53 g, 6.78 mmol)at R.T., and the reaction mixture was stirred at R.T. for 2 h. Themixture was diluted with EA (50 mL), and washed with sat. Na₂S₂O₃solution and NaHCO₃ aq. The organic layer was dried over anhydrousNa₂SO₄, and concentrated to dryness at low pressure. The residue waspurified by prep-HPLC (0.1% HCOOH in water and MeCN) to separate the twoisomers (about 1:1). NOE showed the polar one was 29-8 (0.6 g, 16%) as awhite solid.

To a solution of 29-8 (0.7 g, 1 mmol) in dry pyridine (10 mL) was addedBzCl (147 mg, 1.05 mmol) at 0° C. The mixture was stirred at R.T. for 3h. The mixture was then diluted with EA, and washed with sat. NaHCO₃ aq.and brine. The organic layer was dried over Na₂SO₄, and evaporated atlow pressure. The residue was purified by silica gel column (20% EA inPE) to give 29-9 (0.65 g, 81%) as a white solid.

To a solution of 29-9 (0.65 g, 0.8 mmol) in dry DMF (40 mL) was addedNaOBz (1.15 g, 8 mmol) and 15-crown-5 (1.77 g, 8 mmol). The mixture wasstirred at 100° C. for 48 h. The solvent was evaporated at low pressure,and the residue was dissolved in EA (30 mL), and washed with water andbrine. The organic layer was dried over Na₂SO₄ and concentrated at lowpressure. The residue was purified by silica gel column (20% EA in PE)to give 29-10 (500 mg, 78%) as a white solid.

Compound 29-10 (400 mg, 0.5 mmol) in NH₃/MeOH (7N, 100 mL) was stirredat R.T. for 18 h. The mixture was concentrated at low pressure, and theresidue was purified by silica gel column (5% MeOH in DCM) to give 29-11(220 mg, 63%) as a white solid. ESI-MS: m/z 590.3 [M+H]⁺.

Compound 29-11 (59 mg, 0.1 mmol) was dissolved in 50% TFA in methanol(10 mL), and the mixture was kept at R.T. for 2 h. The solvent wasevaporated and co-evaporated with a methanol/toluene mixture to removetraces of the acid. The residue was suspended in CH₃CN (1 mL) andcentrifuged. The precipitate was washed with CH₃CN (1 mL) and dried.Compound 29 was obtained as a colorless solid (21 mg, 65%. MS: m/z 316.2[M−1]⁻.

Example 16

A freshly prepared EtONa in dry EtOH (2N, 150 mL) was added to asolution of 29-4 (13.67 g, 17.15 mmol) in EtOH (50 mL) at 0° C. Themixture was stirred at R.T. for 1 h, and then concentrated at lowpressure. The residue was purified by silica gel column (5% MeOH in DCM)to give 42-1 (10 g, 98%) as a yellow solid.

To a solution of PPh₃ (2.73 g, 10.4 mol) in anhydrous pyridine (60 mL)was added I₂ (2.48 g, 9.76 mmol) at R.T., and the reaction mixture wasstirred R.T. for 30 mins. A solution of 42-1 (3.9 g, 6.51 mmol) inpyridine (10 mL) was added. The mixture was stirred at R.T. overnight.The reaction was quenched with sat. Na₂S₂O₃ solution and NaHCO₃ aq., andthen extracted with EA (100 mL). The organic layer was dried overanhydrous Na₂SO₄, and evaporated at low pressure. The residue waspurified by silica gel column (2% MeOH in DCM) to give 42-2 (3.0 g, 75%)as a yellowed solid.

To a solution of 42-2 in dry THF (300 mL) was added DBU (14.0 g, 91.8mmol), and the mixture was heated to reflux for 3 h. The mixture wasconcentrated at low pressure. The residue was dissolved in EA (100 mL),and washed with brine. The organic layer was dried over anhydrousNa₂SO₄, and evaporated at low pressure. The residue was purified bysilica gel column (20% EA in PE) to give 42-3 (0.6 g, 37.5%) as a whitesolid.

To an ice-cooled solution of 42-3 (2.0 g, 3.44 mmol) in anhydrous MeCN(20 mL) was added NIS (0.975 g, 4.3 mmol) and TEA.3HF (0.82 g, 5.16mmol) at 0° C. The mixture was stirred at R.T. for 2 h. The reaction wasquenched with sat. Na₂SO₃ and NaHCO₃ aqueous solution, and thenconcentrated at low pressure. The residue was dissolved in EA (50 mL),washed with brine, dried over anhydrous Na₂SO₄, and evaporated at lowpressure. The residue was purified by silica gel column (20% EA in PE)to give 42-4 (1.5 g, 60%) as a white solid.

To a solution of 42-4 (1 g, 1.37 mmol) in dry pyridine (100 mL) wasadded BzCl (0.23 g, 1.65 mmol) at 0° C. The reaction was stirred for 30mins and checked by LCMS. The mixture was concentrated at low pressure,and the residue was dissolved in EA (50 mL). The solution was washedwith brine. The organic layer was dried over MgSO₄, and evaporated atlow pressure. The residue was purified by silica gel columnchromatography (10% EA in PE) to give 42-5 (0.9 g, 78%) as a whitesolid.

To a solution of 42-5 (2 g, 2.4 mmol) in dry DMF (40 mL) was added NaOBz(3.46 g, 24 mmol) and 15-crown-5 (4.5 mL). The mixture was stirred at95° C. for 72 h. The mixture was then diluted with EA (100 mL), andwashed with water and brine. The organic phase was dried over MgSO₄, andconcentrated at low pressure. The residue was purified by silica gelcolumn (15% EA in PE) to give 42-6 (1.5 g, 75%) as a white solid.

Compound 42-6 (1.35 g, 1.64 mmol) in NH₃/MeOH (150 mL) was stirred atR.T. for 18 h. The mixture was concentrated at low pressure, and theresidue was purified by silica gel column (5% MeOH in DCM) to give 42-7(0.9 g, 90%) as a white solid. ESI-MS: m/z 618.3 [M+H]⁺.

To a solution of 42-7 (99 mg, 0.16 mmol) in DCM (1.0 mL), triethylamine(92.7 μL, 0.64 mmol) was added at R.T. The mixture was cooled to 0 to 5°C. (ice/water bath), and freshly prepared and distilled isopropylphosphorodichloridate (36.6 μL, 0.2 mmol, prepared according to aprocedure, Reddy et al. J. Org. Chem. 2011, 76 (10), 3782-3790) wasadded to the mixture. The mixture was stirred 0 to 5° C. (ice/waterbath) for 15 mins, followed by addition of N-methylimidazole (26.3 μL,0.32 mmol). The mixture was then stirred for 1 h at 0 to 5° C. TLCshowed absence of 42-7. EA (100 mL) was added, followed by water. Theorganic layer was washed H₂O, saturated aqueous NH₄Cl solution andbrine. The organic layer was separated, dried over anhydrous MgSO₄ andfiltered. The filtrate was concentrated in vacuum to give a residue,which was purified on silica gel with 0 to 10% iPrOH/DCM to give amixture of 42-a and 42-b (61.5 mg).

A mixture of 42-a and 42-b (61.5 mg, 0.085 mmol) was dissolved inanhydrous CH₃CN (0.5 mL), and 4N HCl in dioxane (64 μL) was added at 0to 5° C. (ice/water bath). The mixture was stirred at R.T. for 40 mins,and anhydrous EtOH (200 μL) was added. The solvents were evaporated atR.T. and co-evaporated with toluene 3 times. The residue was dissolvedin 50% CH₃CN/H₂O, was purified on a reverse-phase HPLC (C18) usingacetonitrile and water, followed by lyophilization to give compound 42(1.8 mg) and compound 43 (14.5 mg).

Compound 42: ¹H NMR (CD₃OD-d₄, 400 MHz) δ 8.0 (s, 1H), 6.69 (d, J=16.0Hz, 1H), 5.9-5.6 (br s, 1H), 4.94-4.85 (m, 1H), 4.68-4.52 (m, 3H),1.49-1.3 (m, 12H); ¹⁹F NMR (CD₃OD-d₄) δ −122.8 (s), −160.06 (s); ³¹P NMR(CD₃OD-d₄) δ −7.97 (s). ESI-LCMS: m/z=450.1 [M+H]⁺; Compound 43: ¹H NMR(CD₃OD-d₄, 400 MHz) δ 7.96 (s, 1H), 6.68 (s, 1H), 6.69 (d, J=16.8 Hz,1H), 6.28-6.1 (br s, 1H), 4.81-4.5 (m, 4H), 1.45-1.39 (m, 12H); ³¹P NMR(CD₃OD-d₄) δ −5.84 (s). ESI-LCMS: m/z=450.0 [M+H]⁺.

Example 17

To a solution of 42-7 (0.47 g, 0.65 mol) in DCM (3 mL) was added AgNO₃(0.22 g, 1.29 mmol), collidine (0.15 g, 1.29 mmol) and MMTrCl (0.3 g,0.974 mmol) at 0° C. The mixture was stirred at R.T. overnight. Themixture was filtered, and the filter was washed with sat. aq. NaHCO₃solution and brine. The organic layer was separated, dried overanhydrous Na₂SO₄ and concentrated at low pressure. The residue waspurified by silica gel column to give 32-1 (0.55, 85%) as a white solid.

To a solution of 32-1 (0.5 g, 0.5 mmol) in dry DMF (10 mL) was addedNaOBz (0.72 g, 5 mmol) and 15-crown-5 (0.9 mL). The mixture was stirredat 95° C. for 72 h. The mixture was diluted with EA, and washed withwater and brine. The organic phase was dried over MgSO₄ and concentratedat low pressure. The residue was purified by silica gel column (10% EAin PE) to give 32-2 (0.3 g, 60%) as a white solid.

Compound 32-2 (0.3 g, 0.3 mmol) in NH₃/MeOH (30 mL) was stirred at R.T.for 18 h. The mixture was concentrated at low pressure, and the residuewas purified by silica gel column (20% EA in PE) to give 32-3 (145 mg,56%) as a white solid. ESI-LCMS: m/z 890.5 [M+H]⁺.

To a stirred solution of 32-3 (161 mg, 0.16 mmol) in anhydrous CH₃CN(2.0 mL) was added N-methylimidazole (118 μL, 2.87 mmol) at 0 to 5° C.(ice/water bath) followed by solution of 32-4 (186 mg, 0.54 mmol,dissolved in 2 mL of CH₃CN). The solution was stirred at 0 to 5° C. for4 h. The mixture was diluted with EA, and water was added (15 mL). Thesolution was washed H₂O, 50% aqueous citric acid solution and brine. Theorganic layer was separated, dried over anhydrous MgSO₄ and filtered.The filtrate was concentrated in vacuum to give a residue, which waspurified on silica gel with 0 to 40% EA/hexanes to give as 32-5 (82.6mg) as the faster eluting isomer and 32-6 (106 mg) as the slower elutingisomer.

Compound 32-5 (82.6 mg, 0.07 mmol) was dissolved in_anhydrous CH₃CN (0.5mL), and 4N HCl in dioxane (35 μL) was added at 0 to 5° C. The mixturewas stirred at R.T. for 1 h, and anhydrous EtOH (100 μL) was added. Thesolvents were evaporated at R.T. and co-evaporated with toluene 3 times.The residue was dissolved in 50% CH₃CN/H₂O, and purified on areverse-phase HPLC (C18) using acetonitrile and water, followed bylyophilization to give compound 32 (19.4 mg). ¹H NMR (CD₃OD-d₄, 400 MHz)δ 7.9 (s, 1H), 7.32-7.28 (t, J=8.0 Hz, 2H), 7.2-7.12 (m, 3H), 6.43 (d,J=17.6 Hz, 1H), 4.70-4.63 (m, 2H), 4.55-4.4 (m, 3H), 3.94-3.9 (m, 1H),1.79-1.67 (m, 4H), 1.53-1.49 (m, 1H), 1.45-1.22 (m, 15H); ³¹P NMR(CD₃OD-d₄) δ 4.06 (s); ESI-LCMS: m/z=655.2 [M+H]⁺, 653.15 [M−H]⁻.

Compound 32-6 (100 mg, 0.083 mmol) was dissolved in_anhydrous CH₃CN (0.5mL), and 4N HCl in dioxane (50 μL) was added at 0 to 5° C. Following theprocedure for obtaining compound 32, compound 33 (31.8 mg) was obtained.¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.93 (s, 1H), 7.33-7.29 (m, 2H), 7.24-7.14(m, 3H), 6.41 (d, J=17.6 Hz, 1H), 4.70-4.60 (m, 2H), 4.54-4.49 (m, 2H),4.44-4.39 (m, 1H), 3.92-3.89 (m, 1H), 1.77-1.66 (m, 4H), 1.54-1.24 (m,16H); ³¹P NMR (CD₃OD-d₄) δ 3.91 (s); ESI-LCMS: m/z=655.2 [M+H]⁺, 653.1[M−H]⁻.

Example 18

Compound 53-1 (70 mg, 58%) was prepared from 32-3 (90 mg; 0.1 mmol) andtriethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.2 mmol)with DIPEA (87 μL), BopCl (44 mg), and 3-nitro-1,2,4-triazole (29 mg) inTHF (2 mL) according to a method described for compound 51-2.Purification was done with hexanes/EtOAc solvent system, 20-80%gradient.

Compound 53 (25 mg, 64%) was prepared from 53-1 (70 mg) in acetonitrile(0.6 mL) and 4 N HCl/dioxane (50 μL) according to a method described forcompound 51. MS: m/z=658 [M+1]⁺.

Example 19

To a mixture of pre-silylated 6-Cl-guanine (using HMDS and (NH₄)₂SO₄)(25.2 g, 150 mmol) in DCE (300 mL) was added 40-1 (50 g, 100 mmol) andTMSOTf (33.3 g, 150 mmol) at 0° C. The mixture was stirred at 70° C. for16 h, and then concentrated at low pressure. The residue wasre-dissolved in EA, and washed with sat. aq. NaHCO₃ and brine. Theorganic layer was dried over anhydrous Na₂SO₄, and concentrated at lowpressure. The residue was purified on silica gel column (PE/EA=2/1) togive pure 40-2 (45 g, 73%) as a white solid.

To a solution of 40-2 (45 g, 73.4 mmol) in EtOH (73 mL) was added withEtONa (1N in EtOH, 360 mL). The mixture was stirred at R.T. for 16 h.The mixture was then concentrated to give a residue, which was purifiedby silica gel column (DCM/MeOH=10/1) to give pure 40-3 (19 g, 83%) as awhite solid.

To a solution of 40-3 (19 g, 61.1 mmol) in pyridine (120 mL) was addedwith TIPDSCl₂ (19.2 g, 61 mmol) dropwise at 0° C. The mixture wasstirred at R.T. for 16 h, and then concentrated at low pressure. Theresidue was re-dissolved in EA, and washed with sat. aq. NaHCO₃. Theorganic layer was dried over anhydrous Na₂SO₄, and concentrated at lowpressure. The residue was purified by silica gel column (DCM/MeOH=20/1)to give pure 40-4 (22 g, 65%) as a white solid.

To a solution of 40-4 (22 g, 39.8 mmol) in DMF/pyridine (5/1, 100 mL)was added TMSCl (12.9 g, 119 mmol) dropwise at 0° C. The mixture wasstirred at R.T. for 1 h and then treated with isobutyryl chloride (5.4g, 50 mmol). The mixture was stirred at R.T. for 3 h and then quenchedby NH₄OH. The mixture was concentrated at low pressure. The residue wasdissolved in EA (200 mL). The solution was washed with sat. aq. NaHCO₃,and then the organic layer was dried and concentrated at low pressure.The residue was purified by silica gel column (DCM/MeOH=50/1) to givepure 40-5 (15 g, 60%) as a white solid.

To a solution of 40-5 (15 g, 24.1 mmol) in DCM (100 mL) was added PDC(13.5 g, 26 mmol) and Ac₂O (9.8 g, 96 mmol) at 0° C. The mixture wasstirred at R.T. for 16 h. The reaction was quenched by sat. aq. NaHCO₃,and then extracted with EA. The organic layer was dried over anhydrousNa2SO4, and concentrated at low pressure. The residue was dissolved inanhydrous THF (100 mL). To a solution of TMSCCH (12 g, 112 mmol) in THF(200 mL) was added n-BuLi (2.5 N, 44 mL) at −78° C. The mixture wasstirred at −78° C. for 15 mins and 0° C. for 15 mins. The mixture wastreated with a solution of crude ketone in THF at −78° C. and stirred at−30° C. for 2 h. The reaction was quenched by sat. aq. NH₄Cl, and thenextracted by EA. The combined organic layer was dried over anhydrousNa₂SO₄, and concentrated at low pressure. The residue was purified bysilica gel column (PE/EA=10/1) to give pure 40-6 (3.1 g, 18%) as a whitesolid.

To a solution of 40-6 (7 g, 7.5 mmol) and pyridine (1.4 g, 17 mmol) inDCM (35 mL) was added with DAST (5.6 g, 35 mmol) at −78° C. The mixturewas stirred at −78° C. for 3 h. The reaction was quenched by sat. aq.NaHCO₃, and then extracted with EA. The combined organic layer was driedover anhydrous, and concentrated at low pressure. The residue waspurified by silica gel column (PE/EA=10/1) to give pure 40-7 (3.1 g,18%) as a white solid.

Compound 40-7 (4.1 g, 5.7 mmol) in sat. NH₃/MeOH (100 mL) was stirred atR.T. for 16 h, and concentrated at low pressure. The residue wasre-dissolved in anhydrous DCM (300 mL), and was treated with AgNO₃ (27.0g, 160 mmol), collidine (22 mL) and MMTrCl (23.0 g, 75.9 mmol) in smallportions under N₂. The mixture was stirred at R.T. for 16 h. The mixturewas filtered, and the filtrate was washed with sat. NaHCO₃ solution andbrine. The organic layer was separated, dried over anhydrous Na₂SO₄, andconcentrated at low pressure. The residue was purified by silica gelcolumn (PE/EA=10/1) to give the pure intermediate. The intermediate wasdissolved in a solution of TBAF/THF (1N, 20 mL). The mixture was stirredat R.T. for 2 h and then concentrated at low pressure. The residue waspurified by silica gel column (DCM/MeOH=50/1) to give pure 40-8 (3.0 g,86%) as a white solid.

To a solution of 40-8 (3.0 g, 4.9 mmol) in THF (50 mL) was addedimidazole (840 mg, 12 mmol), PPh₃ (3.2 g, 12 mmol), and I₂ (2.4 g, 9.2mmol) at 0° C. The mixture was stirred at R.T. for 16 h. The reactionwas quenched by sat. aq. Na₂S₂O₃, and then extracted with EA. Thecombined organic layer was dried over anhydrous Na₂SO₄, and concentratedat low pressure. The residue was purified by silica gel column(PE/EA=2/1) to give crude 40-9 (4.2 g, >100%, containing TPPO) as awhite solid.

To a solution of crude 40-9 in anhydrous THF (30 mL) was added DBU (2.7g, 18 mmol), and heated to 80° C. The mixture was stirred for 1 h andchecked by LCMS. The mixture was quenched by water, and extracted withEA. The organic layer was dried over anhydrous Na₂SO₄ and filtered, andthe filtrate was concentrated at low pressure. The residue was purifiedby silica gel column (PE/EA=2/1) to give 40-10 (2.0 g, 69%) as a whitesolid.

To an ice-cooled solution of 40-10 (2.0 g, 3.38 mmol) in anhydrous MeCN(15 mL) was added NIS (777 mg, 3.5 mmol) and NEt₃.3HF (536 g, 3.3 mmol)at 0° C. The mixture was stirred at R.T. for 16 h and checked by LCMS.After completion, the mixture was quenched by sat. Na₂SO₃ and sat.NaHCO₃ solution, and extracted with EA. The organic layer was separated,dried over anhydrous Na₂SO₄ and concentrated at low pressure. Theresidue was purified by silica gel column chromatography (PE/EA=10/1 to3/1) to give 40-11 (2.1 g, 84.0%) as a white solid.

To a solution of crude 40-11 (2.1 g, 2.85 mmol) in anhydrous DCM (100mL) was added DMAP (490 mg, 4 mmol), and BzCl (580 mg, 4 mmol) at 0° C.The mixture was stirred overnight and checked by LCMS. The reaction waswashed with sat. NaHCO₃ solution. The organic layer was dried overanhydrous Na₂SO₄, and concentrated at low pressure. The residue waspurified by silica gel column chromatography (PE/EA=8/1 to 3/1) to give40-12 (2.0 g, 83.4%) as a white solid.

To a solution of 40-12 (2.0 g, 2.4 mmol) in anhydrous DMF (60 mL) wasadded NaOBz (3.3 g, 23.0 mmol) and 15-crown-5 (5.11 g, 23 mmol). Themixture was stirred at 110° C. for 36 h. The reaction was quenched bywater, and the mixture was extracted with EA. The organic layer wasdried over anhydrous Na₂SO₄, and concentrated at low pressure. Theresidue was purified by silica gel column (PE/EA=5/1 to 3/1) to give40-13 (830 mg, 42.0%) as a white solid. ESI-MS: m/z 836.11 [M+H]⁺.

A solution of 40-13 (831 mg, 1.0 mmol) in anhydrous n-butylamine (4 mL)was stirred at R.T. for 3 h under N₂ atmosphere. The reaction wasmonitored by TLC. The solvent was evaporated in vacuo, and the residuewas purified by silica gel column (MeOH in DCM from 0% to 10%) to givethe crude product, which as re-purified using silica gel column to give40-14 as a light pink solid (563 mg).

To a solution of 40-14 (560 mg, 0.89 mmol) in anhydrous pyridine (5 mL)was added imidazole (78.6 mg, 1.16 mmol) and TBSCl (202 mg, 1.34 mmol)at 0 to 5° C. The mixture was stirred at R.T. for 15 h. The reaction wasquenched by adding absolute EtOH (0.3 mL). The solution was concentratedto dryness under reduced pressure, and co-evaporated with toluene 3times. The residue was dissolved in EA (150 mL), and washed with water,sat. NaHCO₃, and brine. The combined organic layer was dried overNa₂SO₄, filtered and evaporated at low pressure. The residue waspurified by silica gel column (0-20% EA in hexanes) to give 40-15 (303mg) as a white solid.

To a solution of 40-15 (303 mg, 0.41 mmol), AgNO₃ (208 mg, 1.23 mmol)and collidine (0.55 mL, 4.51 mmol) in anhydrous DCM (4 mL) was addedMMTrCl (378 mg, 1.3 mmol) under N₂. The mixture was stirred at R.T.overnight under N_(2,) and monitored by TLC. The mixture was filteredthrough pre-packed celite filter, and the filtrate was washed with waterand, 50% aqueous citric acid, and brine. The organic layer wasseparated, dried over anhydrous Na₂SO₄, filtered and concentrated at lowpressure. The residue was purified by silica gel column (EA in hexanesfrom 0% to 30%) to give 40-16 (374 mg, 90%).

To a solution of 40-16 (374 mg, 0.37 mmol) in anhydrous THF (4 mL) wasadded 1.0 M solution of TBAF (0.74 mL, 0.74 mmol) at 0 to 5° C. Themixture was stirred at R.T. for 1 h. The mixture was quenched withsilica gel, and filtered. The solvents were evaporated to give the crudeproduct, which was purified by silica gel column (EA in hexanes from 0%to 50%) to give 40-17 (265 mg).

To a stirred solution of 40-17 (187.5 mg, 0.16 mmol) in anhydrous CH₃CN(2.5 mL) was added N-methylimidazole (136 μL, 1.66 mmol) at 0-5° C.(ice/water bath) followed by solution of phenyl(cyclohexanoxy-L-alaninyl)phosphorochloridate (214 mg, 0.62 mmol,dissolved in 0.5 mL of CH₃CN). The solution was stirred at R.T. for 3 h,and then diluted with EA followed by the addition of water (15 mL). Thesolution was washed with H₂O, 50% aqueous citric acid solution andbrine. The organic layer was separated, dried over anhydrous MgSO₄ andfiltered. The filtrate was concentrated in vacuum to give a residue,which was purified on silica gel with 0 to 40% EA/hexanes to give(single isomers) of 40-18 (108 mg) Elution of the latter fraction gave(single isomers) of 40-19 (120 mg) as glassy solid.

Compound 40-18 (108 mg, 0.089 mmol) was dissolved in_anhydrous CH₃CN(0.5 mL), and 4N HCl in dioxane (67 μL) was added at 0 to 5° C.(ice/water bath). The mixture was stirred at R.T. for 40 mins, andanhydrous EtOH (200 μL) was added. The solvents were evaporated at R.T.and co-evaporated with toluene 3 times. The residue was dissolved in 50%CH₃CN/H₂O, was purified on a reverse-phase HPLC (C18) using acetonitrileand water, followed by lyophilization to give compound 40 (26.6 mg) as awhite foam. ¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.89 (s, 1H), 7.33-7.29 (m,2H), 7.20-7.13 (m, 3H), 7.17 (m, 1H), 6.62 (d, J=15.6 Hz, 1H), 5.39 (t,J=25.2 Hz, 1H), 4.75-4.42 (m, 6H), 3.92 (t, J=8.8 Hz, 1H), 3.24 (d,J=5.6 Hz, 1H), 1.76-1.51 (m, 5H), 1.45-1.25 (m, 12H); ³¹P NMR (CD₃OD-d₄)δ 4.04 (s); ESI-LCMS: m/z=665.2 [M+H]⁺.

Compound 41 (44.4 mg, single isomer) was obtained according to theprocedure described for compound 40 using 40-19. ¹H NMR (CD₃OD-d₄, 400MHz) δ 7.93 (s, 1H),), 7.32 (t, J=8.0 Hz, 1H), 7.24 (d, J=7.6 Hz, 2H),7.16 (t, J=7.6 Hz, 1H), 6.61 (d, J=16.0 Hz, 1H), 4.68-4.60 (m, 2H),4.54-4.39 (m, 3H), 3.93-3.89 (m, 1H), 3.24 (d, J=5.6 Hz, 1H), 1.75-1.5(m, 5H), 1.48-1.23 (m, 12H); ¹⁹F NMR (CD₃OD-d₄) δ −122.95 (s),−155.84-155.99 (m); ³¹P NMR (CD₃OD-d₄) δ 3.94 (s); ESI-LCMS: m/z=665.15[M+H]⁺.

Example 20

To a solution of triethylammoniumbis(isopropyloxycarbonyloxymethyl)phosphate (0.33 mmol, prepared from110 mg of bis(POC)phosphate and 46 μL of Et₃N) in THF was added 49-1 (91mg, 0.11 mmol). The mixture evaporated and rendered anhydrous byco-evaporating with pyridine follow by toluene. The residue wasdissolved in anhydrous THF (1.5 mL) and cooled in an ice-bath.Diisopropylethyl amine (0.19 mL, 10 eq.) was added, followed by BOP—Cl(0.14 g, 5 eq.), and 3-nitro-1,2,4-triazole (63 mg, 5 eq.). The mixturewas stirred 0° C. for 90 mins, diluted with EtOAc (30 mL), washed withsat. aq. NaHCO₃, brine, and dried (Na₂SO₄). The residue was purified onsilica (10 g column) with CH₂Cl₂/i-PrOH solvent system (2-10% gradient)to obtain 49-2 (13 mg, 10%) and 49-3 (95 mg, 58%).

A solution of 49-2 and 49-3 (13 mg and 95 mg, respectively) in 80% aq.HCOOH (3 mL) was stirred at R.T. for 3 h, then evaporated andco-evaporated with toluene. The residue was purified on silica (10 gcolumn) with CH₂Cl₂/MeOH (4-10% gradient) to obtain compound 49 in (42mg, 94%) yield. MS: m/z=628 [M+1]⁺.

Example 21

Compound 52-2 (158 mg, 50%) was from 52-1 (0.21 g; 0.35 mmol) andtriethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.54 mmol)with DIPEA (0.18 mL), BopCl (178 mg), and 3-nitro-1,2,4-triazole (80 mg)in THF (4 mL).

A solution of 52-2 (158 mg) in acetonitrile (1 mL) and HCl (4 N/dioxane;85 μL) was stirred at R.T. for 30 mins. The reaction was quenched withMeOH and concentrated. The residue was purified on silica gel (10 gcolumn) with CH₂Cl₂/i-PrOH (3-10% gradient) to give compound 52 (85 mg,76%). MS: m/z=656 [M+1]⁺.

Example 22

A mixture of 11-1 (170 mg, 0.19 mmol) and methanolic ammonia (7 N; 3 mL)was stirred at R.T. for 8 h, concentrated and purified on silica gel (10g column) with CH₂Cl₂/MeOH (4-11% gradient) to give 11-2 (100 mg, 90%).

Compound 11-2 was rendered anhydrous by co-evaporating with pyridine,followed by toluene. To a solution of 11-2 (24 mg, 0.04 mmol), andN-methylimidazole (17 μL, 5 eq.) in acetonitrile (1 mL) was added thephosphorochloridate (50 mg, 3.5 eq.) in 2 portions in 6 h intervals. Themixture was stirred at R.T. for 1 d and evaporated. Purification onsilica (10 g column) with CH₂Cl₂/MeOH (4-12% gradient) yielded 11-3 (10mg, 28%).

A solution of 11-3 (9 mg, 0.01 mmol) in 80% formic acid was stirred 3 hat R.T. The mixture was evaporated and purified on silica (10 g column)with CH₂Cl₂/MeOH (5-15% gradient) to give compound 11 (3 mg, 50%). MS:m/z=624 [M−1]⁻.

Example 23

A mixture of 14-1 (1.2 g, 4.3 mmol), PTSA monohydrate (0.82 g, 1 eq.),and trimethyl orthoformate (14 mL, 30 eq.) in dioxane (30 mL) wasstirred overnight at R.T. The reaction was neutralized with 7 N NH₃/MeOHand a white solid removed by filtration. The residue was dissolved inTHF (10 mL) and treated with 80% aq. AcOH (5 mL). The mixture was keptat R.T. for 45 mins and then evaporated. The residue was purified onsilica gel (25 g column) with CH₂Cl₂/MeOH (4-10% gradient) to give 14-2(1.18 g, 87%).

Compound 14-3 (137 mg, 75%) was prepared from 14-2 (93 mg, 0.29 mmol)and triethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.44mmol) with DIPEA (0.2 mL), BopCl (147 mg), and 3-nitro-1,2,4-triazole(66 mg) in THF (3 mL). Purification was done with CH₂Cl₂/i-PrOH solventsystem (3-10% gradient).

A solution of 14-3 (137 mg) in 80% aq. HCOOH was stirred at R.T. for 2h, and then concentrated. The residue was co-evaporated with toluene andthen MeOH containing a small amount of a small amount of Et₃N (2 drops).Purification on silica (25 g column) with CH₂Cl₂/MeOH (4-10% gradient)gave compound 14 (100 mg, 77%). MS: m/z=1175 [2M−1]⁻.

Example 24

Compound 16-1 (50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol)were co-evaporated with anhydrous toluene 3 times. To a solution of 10-1in MeCN (200 mL) was added DBU (39.5 g, 258.0 mmol) at 0° C. The mixturewas stirred at 0° C. for 30 mins, and then TMSOTf (95.5 g, 430.0 mmol)was added dropwise at 0° C. The mixture was stirred at 0° C. for 30mins. The mixture was heated to 70° C., and stirred overnight. Thesolution was cooled to R.T. and diluted with EA (100 mL). The solutionwas washed with sat. NaHCO₃ solution and brine. The organic layer wasdried over Na₂SO₄, and concentrated at low pressure. The residue waspurified by column on silica gel (EA in PE from 10% to 40%) to give 16-2(48.0 g, yield: 88.7%) as a yellow foam. ESI-MS: m/z 628 [M+H]⁺.

To a solution of 16-2 (48.0 g, 76.4 mol), AgNO₃ (50.0 g, 294.1 mmol) andcollidine (40 mL) in anhydrous DCM (200 mL) was added MMTrCl (46.0 g,149.2 mmol) in small portions under N₂. The mixture was stirred at R.T.for 3 h under N₂. The reaction was monitored by TLC. The mixture wasfiltered, and the filter was washed with sat. NaHCO₃ solution and brine.The organic layer was dried over anhydrous Na₂SO₄, and concentrated atlow pressure. The residue was purified by silica gel column (EA in PEfrom 5% to 50%) to the give crude 16-3 (68 g, 98%). ESI-MS: m/z 900.1[M+H]⁺.

Sodium (8.7 g, 378.0 mmol) was dissolved in dry EtOH (100 mL) at 0° C.,and slowly warmed to R.T. Compound 16-3 (68.0 g, 75.6 mmol) was treatedwith freshly prepared NaOEt solution, and stirred overnight at R.T. Thereaction was monitored by TLC, and the mixture was concentrated at lowpressure. The mixture was diluted with H₂O (100 mL), and extracted withEA (3×100 mL). The organic layer was dried over anhydrous Na₂SO₄, andevaporated at low pressure. The residue was purified by silica gelcolumn chromatography (MeOH in DCM from 1% to 5%) to give 16-4 (34.0 g,75.2%) as a yellow solid. ESI-MS: m/z 598 [M+H]⁺.

Compound 16-4 (32.0 g, 53.5 mmol) was co-evaporated with anhydrouspyridine 3 times. To an ice-cooled solution of 16-4 in anhydrouspyridine (100 mL) was added TsCl (11.2 g, 58.9 mmol) in pyridine (50 mL)dropwise at 0° C. The mixture was stirred for 18 h. at 0° C. Thereaction was checked by LCMS (about 70% was the desired product). Thereaction was quenched with H₂O, and the solution was concentrated at lowpressure. The residue was dissolved in EA (100 mL), and washed with sat.NaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄, andevaporated at low pressure. The residue was purified by silica gelcolumn chromatography (MeOH in DCM from 1% to 5%) to give crude 16-5(25.0 g, 62.2%) as a yellow solid. ESI-MS: m/z 752 [M+H]⁺.

To a solution of 16-5 (23.0 g, 30.6 mmol) in acetone (150 mL) was addedNaI (45.9 g, 306.0 mmol) and TBAI (2.0 g), and refluxed overnight. Thereaction was monitored by LCMS. After the reaction was complete, themixture was concentrated at low pressure. The residue was dissolved inEA (100 mL), washed with brine, and dried over anhydrous Na₂SO₄. Theorganic solution was evaporated at low pressure. The residue waspurified by silica gel column chromatography (DCM: MeOH=100:1 to 20:1)to give the crude product. To a solution of the crude product in dry THF(200 mL) was added DBU (14.0 g, 91.8 mmol), and heated to 60° C. Themixture was stirred overnight, and checked by LCMS. The reaction wasquenched with sat. NaHCO₃, and the solution was extracted with EA (100mL). The organic layer was dried over anhydrous Na₂SO₄, and evaporatedat low pressure. The residue was purified by silica gel columnchromatography (MeOH in DCM from 1% to 5%) to give 16-6 (12.0 g, 67.4%)as a yellow solid. ESI-MS: m/z 580 [M+H]⁺.

To an ice-cooled solution of 16-6 (8.0 g, 13.8 mmol) in dry MeCN (100mL) was added NIS (3.9 g, 17.2 mmol) and TEA.3HF (3.3 g, 20.7 mmol) at0° C. The mixture was stirred at R.T. for 18 h and checked by LCMS.After the reaction was complete, the reaction was quenched with satNa₂SO₃ and sat. NaHCO₃ solution. The solution was extracted with EA. Theorganic layer was dried over anhydrous Na₂SO₄, and evaporated at lowpressure. The residue was purified by silica gel column chromatography(EA in PE from 10% to 50%) to give 16-7 (7.2 g, 72.0%) as a solid.ESI-MS: m/z 726 [M+H]⁺.

To a solution of crude 16-7 (7.2 g, 9.9 mmol) in dry DCM (100 mL) wasadded DMAP (3.6 g, 29.8 mmol), and BzCl (2.8 g, 19.8 mmol) at 0° C. Themixture was stirred overnight, and checked by LCMS. The mixture waswashed with sat. NaHCO₃ solution. The organic layer was dried overanhydrous Na₂SO₄, and evaporated at low pressure. The residue waspurified by silica gel column chromatography (EA in PE from 10% to 30%)to give 16-8 (8.0 g, 86.4%) as a solid. ESI-MS: m/z 934 [M+H]⁺.

To a solution of 16-8 (7.5 g, 8.0 mmol) in dry DMF (100 mL) was addedNaOBz (11.5 g, 80.0 mmol) and 15-crown-5 (15.6 mL). The mixture wasstirred for 36 h. at 90° C. The mixture was diluted with H₂O (100 mL),and extracted with EA (3×150 mL). The organic layer was dried overanhydrous Na₂SO₄, and evaporated at low pressure. The residue waspurified by silica gel column chromatography (EA in PE from 10% to 30%)to give crude 16-9 (6.0 g, 80.0%) as a solid. ESI-MS: m/z 928 [M+H]⁺.

Compound 16-9 (4.0 g, 4.3 mmol) was co-evaporated with anhydrous toluene3 times, and treated with NH₃/MeOH (50 mL, 4N) at R.T. The mixture wasstirred for 18 h at R.T. The reaction was monitored by LCMS, and themixture was concentrated at low pressure. The residue was purified bysilica gel column chromatography (EA in PE from 30% to 50%) to give16-10 (1.9 g, 71.7%) as a solid. ESI-MS: m/z 616 [M+H]⁺.

Compound 16-10 (300.0 mg, 0.49 mmol) was co-evaporated with anhydroustoluene 3 times, and was dissolved in MeCN (2 mL). The mixture wastreated with NMI (120.5 mg, 1.47 mmol) and the phosphorochloridatereagent (338.1 mg, 0.98 mmol) in MeCN (1 mL) at 0° C. The mixture wasstirred for 18 h at R.T. The reaction was monitored by LCMS. The mixturewas diluted with 10% NaHCO₃ solution, and extracted with EA. The residuewas purified by silica gel column chromatography (EA in PE from 30% to50%) to give 16-11 (240 mg, 53.3%) as a solid. ESI-MS: m/z 925 [M+H]⁺.

Compound 16-11 (240.0 mg, 0.26 mmol) was treated with 80% AcOH (10 mL),and the mixture was stirred for 18 h at R.T. The reaction was monitoredby LCMS. The mixture was concentrated at low pressure. The residue waspurified by silica gel column chromatography (MeOH in DCM from 1% to 3%)to give compound 16 (87.6 mg, 51.7%) as a solid. ESI-MS: m/z 653 [M+H]⁺.

Example 25

To a stirred solution of compound 25 (60 mg, 0.22 mmol) in anhydrous THF(2.0 mL) was added N-methylimidazole (0.142 mL, 1.73 mmol) at 0° C. (dryice/acetone bath) followed by solution of phenyl(cyclohexanoxy-L-alaninyl)phosphorochloridate (235 mg, 0.68 mmol,dissolved in THF (2 mL). The resulting solution was stirred at 0° C. for1 h, and the temperature was raised up-to 10° C. over the next 1 h. Thereaction left at 10° C. for 3 h. The mixture was cooled to 0 to 5° C.,diluted with EA, and water (5 mL) was added. The solution was washedwith H₂O and brine. The organic layer was separated, dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuumto give a residue, which dissolved in 25% CH₃CN/H₂O. The compound waspurified on a reverse-phase HPLC (C18) using acetonitrile and water,followed by lyophilization gave a white foam. The produce wasre-dissolved in EtOAc, washed with 50% aqueous citric acid solution,dried over anhydrous MgSO₄ and filtered. The filtrate was concentratedin vacuum, and lyophilized to give two isomers (Rp/Sp) of compound 30(6.3 mg). MS: m/z 586.05 [M−H]⁻.

Example 26

Compound 17-1 (50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol)were co-evaporated with anhydrous toluene 3 times. To a solution of 17-1(50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol) in MeCN (200 mL)was added DBU (39.5 g, 258.0 mmol) at 0° C. The mixture was stirred at0° C. for 30 mins, and TMSOTf (95.5 g, 430.0 mmol) was added dropwise at0° C. The mixture was stirred at 0° C. for 30 mins until a clearsolution was observed. The mixture was heated to 70° C., and stirredovernight. The solution was cooled to R.T., and diluted with EA (100mL). The solution was washed with sat. NaHCO₃ solution and brine. Theorganic layer was dried over Na₂SO₄, and concentrated at low pressure.The residue was purified by column on silica gel (EA in PE from 10% to40%) to give 17-2 (48.0 g, 88.7%) as a yellow foam. ESI-MS: m/z 628[M+H]⁺.

To a solution of 17-2 (48.0 g, 76.4 mol), AgNO₃ (50.0 g, 294.1 mmol) andcollidine (40 mL) in anhydrous DCM (200 mL) was added MMTrCl (46.0 g,149.2 mmol) in small portions under N₂. The mixture was stirred at R.T.for 3 h under N₂. Completion of the reaction was determined by TLC.After filtration, the filtrate was washed with sat. NaHCO₃ solution andbrine. The organic layer was dried over anhydrous Na₂SO₄, andconcentrated at low pressure. The residue was purified by silica gelcolumn (EA in PE from 5% to 50%) to the give crude 17-3 (68 g, 98%).ESI-MS: m/z 900.1 [M+H]⁺.

Sodium (8.7 g, 378.0 mmol) was dissolved in dry EtOH (100 mL) at 0° C.,and slowly warmed to R.T. Compound 17-3 (68.0 g, 75.6 mmol) was treatedwith freshly prepared NaOEt solution, and stirred overnight at R.T.Completion of the reaction was determined by TLC and LCMS. The mixturewas concentrated at a low pressure, diluted with H₂O (100 mL), andextracted with EA (3×100 mL). The organic layer was dried over anhydrousNa₂SO₄, and evaporated at low pressure. The residue was purified bysilica gel column chromatography (MeOH in DCM from 1% to 5%) to give17-4 (34.0 g, 75.2%) as a yellow solid. ESI-MS: m/z 598 [M+H]⁺.

Compound 17-4 (32.0 g, 53.5 mmol) was co-evaporated with anhydrouspyridine 3 times. To an ice-cooled solution of 17-4 (32.0 g, 53.5 mmol)in anhydrous pyridine (100 mL) was added a solution of TsCl (11.2 g,58.9 mmol) in pyridine (50 mL) dropwise at 0° C. The mixture was stirredfor 18 h. at 0° C. The reaction was monitored by LCMS, and quenched withH₂O. The solution was concentrated at low pressure, and the residue wasdissolved in EA (100 mL), and washed with sat. NaHCO₃ solution. Theorganic layer was dried over anhydrous Na₂SO₄, and evaporated at a lowpressure. The residue was purified by silica gel column chromatography(MeOH in DCM from 1% to 5%) to give crude 17-5 (25.0 g, 62.2%) as ayellow solid. ESI-MS: m/z 752 [M+H]⁺.

To a solution of 17-5 (23.0 g, 30.6 mmol) in acetone (150 mL) was addedNaI (45.9 g, 306.0 mmol) and TBAI (2.0 g), and the mixture was refluxedovernight. Completion of the reaction was determined by LCMS. Themixture was concentrated at low pressure, and the residue was dissolvedin EA (100 mL). The solution was washed with brine, and dried overanhydrous Na₂SO₄. The organic solution was evaporated at low pressure,and the residue was purified by silica gel column chromatography (DCM:MeOH=100:1 to 20:1) to give a crude product. To a solution of the crudeproduct in dry THF (200 mL) was added DBU (14.0 g, 91.8 mmol), and themixture was heated to 60° C. and stirred overnight. The reaction wasmonitored by LCMS. The reaction was quenched with sat. NaHCO₃ solution,and the solution was extracted with EA (100 mL). The organic layer wasdried over anhydrous Na₂SO₄, and evaporated at low pressure. The residuewas purified by silica gel column chromatography (MeOH in DCM from 1% to5%) to give 17-6 (12.0 g, 67.4%) as a yellow solid. ESI-MS: m/z 580[M+H]⁺.

To an ice-cooled solution of 17-6 (8.0 g, 13.8 mmol) in anhydrous MeCN(100 mL) was added NIS (3.9 g, 17.2 mmol) and TEA.3HF (3.3 g, 20.7 mmol)at 0° C. The mixture was stirred at R.T. for 18 h, and the reaction waschecked by LCMS. After the reaction was completed, the reaction wasquenched with sat. Na₂SO₃ solution and sat. NaHCO₃ solution. Thesolution was extracted with EA (3×100 mL). The organic layer was driedover anhydrous Na₂SO₄, and evaporated at low pressure. The residue waspurified by silica gel column chromatography (EA in PE from 10% to 50%)to give 17-7 (7.2 g, 72.0%) as a solid. ESI-MS: m/z 726 [M+H]⁺.

To a solution of 17-7 (7.2 g, 9.9 mmol) in dry DCM (100 mL) was addedDMAP (3.6 g, 29.8 mmol), and BzCl (2.8 g, 19.8 mmol) at 0° C. Themixture was stirred overnight, and checked by LCMS. The mixture waswashed with sat. NaHCO₃ solution. The organic layer was dried overanhydrous Na₂SO₄, and evaporated at low pressure. The residue waspurified by silica gel column chromatography (EA in PE from 10% to 30%)to give 17-8 (8.0 g, 86.4%) as a solid. ESI-MS: m/z 934 [M+H]⁺.

To a solution of 17-8 (7.5 g, 8.0 mmol) in dry DMF (100 mL) was addedNaOBz (11.5 g, 80.0 mmol) and 15-crown-5 (15.6 mL). The mixture wasstirred for 36 h. at 90° C. The mixture was diluted with H₂O (100 mL),and extracted with EA (3×150 mL). The organic layer was dried overanhydrous Na₂SO₄, and evaporated at low pressure. The residue waspurified by silica gel column chromatography (EA in PE from 10% to 30%)to give crude 17-9 (6.0 g, 80.0%) as a solid. ESI-MS: m/z 928 [M+H]⁺.

Compound 17-9 (4.0 g, 4.3 mmol) was co-evaporated with anhydrous toluene3 times, and treated with NH₃/MeOH (50 mL, 4N) at R.T. The mixture wasstirred for 18 h. at R.T. Completion of the reaction was determined byLCMS. The mixture was concentrated at low pressure, and the residue waspurified by silica gel column chromatography (EA in PE from 30% to 50%)to give product 17-10 (1.9 g, 71.7%) as a solid. ESI-MS: m/z 616 [M+H]⁺.

Compound 17-10 (300.0 mg, 0.49 mmol) was co-evaporated with anhydroustoluene 3 times, and was dissolved in MeCN (2 mL). The mixture wastreated with NMI (120.5 mg, 1.47 mmol) and the phosphorochloridatereagent (326.3 mg, 0.98 mmol) in MeCN (1 mL) at 0° C. The mixture wasstirred for 18 h at R.T. and monitored by LCMS. The mixture was dilutedwith 10% NaHCO₃ solution, and extracted with EA (3×30 mL). The residuewas purified by silica gel column chromatography (EA in PE from 30% to50%) to give 17-11 (210 mg, 47.5%) as a solid. ESI-MS: m/z 913.0 [M+H]⁺.

Compound 17-11 (210 mg, 0.26 mmol) was treated with 80% of AcOH (15 mL),and the mixture was stirred for 18 h at R.T. Completion of the reactionwas determined by LCMS. The mixture was concentrated at low pressure,and the residue was purified by silica gel column chromatography (MeOHin DCM from 1% to 3%) to give compound 17 (71.8 mg, 48.7%) as a solid.ESI-MS: m/z 641.3 [M+H]⁺.

Example 27 Compounds 9, 12, 15, 26, 28, 38, 44, 46, 50, 63, 64, 69 and76

Compounds 9, 12, 15, 26, 28, 38, 44, 46, 50, 63, 64, 69 and 76 wereprepared in a manner similar to method for preparing compound 6. Afterthe addition of POCl₃, the mixture was kept at R.T. for 20-40 mins. Thereaction was controlled by LCMS and monitored by the appearance ofcorresponding nucleoside 5′-monophosphate. After completion of thereaction, tetrabutylammonium salt of pyrophosphate (150 mg) was added,followed by DMF (0.5 mL) to get a homogeneous solution. After 1.5 h atambient temperature, the reaction was diluted with water (10 mL). Thetriphosphate (eluted at 75-80% B) were obtained as described forcompound 6.

MS ³¹P NMR Structure [M − 1]⁻ P(α) P(β) P(γ)

  28 556.2 −10.92 −11.03(d) −23.18(t) −11.86 −11.98(d)

  38 516.1  −7.49  −7.61(d) −22.42(t) −12.17 −12.30(d)

   9 554.0 −10.94 −11.06(d) −23.25(t) −11.85 −11.97(d)

  12 525.2  −8.53(bs) −22.61(bs) −12.17 −12.29(d)

  15 564.4 −11.05(bs) −23.25(bs) −11.96 −12.08(d)

  44 566.0 −10.92 −11.04(d) −23.18(t) −11.93  −1(d)

  46 533.3 −10.89 −11.01(d) −23.31(t) −12.49  −1(d)

  50 513.8  −8.66(bs) −22.80(t) −12.17 −12.29(d)

  26 517.7 −13.73 −13.60(d) −25.98(t) −15.18 −15.06(d)

  63 539.5  −7.42 (br · s) −22.57(t) −12.23 −12.34(d)

  64 513.1  −6.36  −6.49(d) −22.49(t) −12.20 −12.33(d)

  69 526.8 −10.96 −11.08(d) −23.33(t) −12.41 −12.53(d)

  76 533.4 −10.78 (br · s) −23.22(t) −12.24 −12.36(d)

The following compounds can also be prepared using a method similar tothe method described in Example 27:

Example 28

Compound 10-1 (5 g, 8.79 mmol) was co-evaporated with anhydrouspyridine. To an ice-cooled solution of 10-1 in anhydrous pyridine (15mL) was added TsCl (3.43 g, 17.58 mmol), and stirred for 1 h at 0° C.The reaction was checked by LCMS and TLC. The reaction was quenched withH₂O, and extracted with EA. The organic phase was dried over anhydrousNa₂SO₄, and evaporated at low pressure. Compound 10-2 (6.35 g, 100%) wasused for next step directly.

To a solution of 10-2 (31.77 g, 43.94 mmol) in acetone (300 mL) wasadded NaI (65.86 g, 439.4 mmol), and heated to reflux overnight. Thereaction was checked by LCMS. The reaction was quenched with sat.Na₂S₂O₃ solution, and extracted with EA. The organic layer was driedover anhydrous Na₂SO₄, and evaporated at low pressure. The residue waspurified by silica gel column chromatography (MeOH in DCM from 1% to 6%)to give 10-3 (11.5 g, 38%) as a white solid.

To a solution of 10-3 (11.5 g, 16.94 mmol) in dry THF (120 mL) was addedDBU (12.87 g, 84.68 mmol), and heated to 60° C. The reaction was stirredovernight and checked by LCMS. The reaction was quenched with sat.NaHCO₃ solution, and extracted with EA. The organic phase was dried overanhydrous Na₂SO₄, and evaporated at low pressure. The residue waspurified by silica gel column chromatography (MeOH in DCM from 1% to 5%)to give 10-4 (5.5 g, 54%) as a white solid.

To an ice-cooled solution of 10-4 (500 mg, 0.90 mmol) in dry DCM (20 ml)was added AgF (618 mg, 4.9 mmol) and a solution of I₂ (500 mg, 1.97mmol) in dry DCM (20 mL). The reaction was stirred for 3 h., and checkedby LCMS. The reaction was quenched with sat Na₂S₂O₃ solution and sat.NaHCO₃ solution, and the mixture was extracted with DCM. The organiclayer was dried by anhydrous Na₂SO₄, and evaporated at low pressure togive crude 10-5 (420 mg, 66%).

To a solution of crude 10-5 (250 mg, 0.36 mmol) in dry DCM (8 mL) wasadded DMAP (0.28 g, 2.33 mmol), TEA (145 mg, 1.44 mmol) and BzCl (230mg, 1.62 mmol) in a solution of DCM (2 mL). The reaction was stirredovernight, and checked by LCMS. The mixture was washed with sat. NaHCO₃solution and brine. The organic layer was evaporated at low pressure.The residue was purified by prep-TLC to give crude 10-6 (150 mg, 46%).

To a solution of crude 10-6 (650 mg, 0.72 mmol) in dry HMPA (20 mL) wasadded NaOBz (1.03 g, 7.2 mmol) and 15-crown-5 (1.59 g, 7.2 mmol). Thereaction was stirred for 2 d at 60° C. The mixture was diluted with H₂O,and extracted with EA. The organic layer was evaporated at low pressure.The residue was purified by prep-TLC to give 10-7 (210 mg, 32.4%).ESI-MS: m/z: 900.4 [M+H]⁺.

A mixture of 10-7 (25 mg) and BuNH₂ (0.8 mL) was stirred overnight atR.T. The mixture was evaporated and purified on silica gel (10 g column)with CH₂Cl₂/MeOH (4-15% gradient) to yield 10-8 (15 mg, 91%).

A mixture of 10-8 (15 mg, 0.02 mmol) in ACN (0.25 mL) and 4 NHCL/dioxane (19 uL) was stirred at R.T. for 45 mins. The mixture wasdiluted with MeOH and evaporated. The crude residue was treated withMeCN, and the solid was filtered to yield compound 10 (7 mg). MS:m/z=314 [M−1]⁻.

Example 29

To a solution of 36-1 (150 mg, 0.24 mmol) in DCM (2.0 mL), triethylamine(141 μL, 2.0 mmol) was added at R.T. The mixture was cooled to 0 to 5°C. (ice/water bath), and freshly prepared and distilled isopropylphosphorodichloridate (45 μL, 0.26 mmol, prepared according to aprocedure, Reddy et al. J. Org. Chem. 2011, 76 (10), 3782-3790) wasadded. The mixture was stirred at 0 to 5° C. (ice/water bath) for 15mins, followed by N-methylimidazole (40 μL, 0.49 mmol). The mixture wasstirred for 1 h at 0 to 5° C. TLC showed the absence of startingmaterial 36-1. EA (100 mL) was added, followed by water. The organiclayer was washed with H₂O, sat. aq. NH₄Cl solution and brine. Theorganic layer was separated, dried over anhydrous MgSO₄ and filtered.The filtrate was concentrated in vacuum to give a residue, which waspurified on silica gel with 0 to 10% iPrOH/DCM to give 36-2a (16.9 mg,faster eluting isomer) and 36-2b (72.7 mg, slower eluting isomer).

Compounds 36-2a and 36-2b were deprotected using a procedure describedherein. Compound 36 (7.3 mg, single isomers from 36-2a (16.5 mg, 0.0235mmol)) and compound 37 (29.0 mg. single isomers from 36-2b (72.7 mg, 0.1mmol)) were obtained.

Compound 36: ¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.94 (s, 1H), 6.32 (s, 1H),6.00-5.9 (br s, 1H), 4.9-4.487 (m, 1H), 4.83-4.77 (m, 1H), 4.65-4.50 (m,3H), 1.45-1.39 (s, 9H), 1.2 (s, 3H); ¹⁹F NMR (CD₃OD-d₄) δ −120.3 (s);³¹P NMR (CD₃OD-d₄) 8-5.19 (s); ESI-LCMS: m/z=448.05 [M+H]⁺. Compound 37:¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.98 (s, 1H), 6.34 (s, 1H), 5.78-5.64 (brs, 1H), 4.95-4.48 (m, 2H), 4.62-4.52 (m, 3H), 1.48-1.42 (s, 9H), 1.1 (s,3H); ¹⁹F NMR (CD₃OD-d₄) δ −121.3 (s); ³¹P NMR (CD₃OD-d₄) δ −7.38 (s);ESI-LCMS: m/z=448.05 [M+H]⁺.

Example 30

To a solution of 48-1 (600 mg, 1.29 mmol) in anhydrous CH₃CN (4 mL) wasadded DMAP (315 mg, 2.59 mmol), TEA (391 mg, 3.87 mmol) and TPSCl (782mg, 2.58 mmol). The mixture was stirred for 3 h. under N₂. A solution ofNH₃ in THF (2 mL) was added, and stirred for 1 h. The reaction wasquenched with sat. NH₄Cl solution, and extracted with EA. The organiclayer was dried over anhydrous Na₂SO₄, and concentrated to dryness atlow pressure. The residue was purified by column chromatography toprovide 48-2 (370 mg, 62%) as a white foam solid.

Compound 48-2 (370 mg, 1.48 mmol) in methanolic ammonium was stirred atR.T. for 4 h. The solution was concentrated to dryness to give compound48 (200 mg, 91%) as a white solid. ESI-MS: m/z 275.9 [M+H]⁺.

Example 31

The diastereomers of compound 2 were separated by RP-HPLC. A gradient of10-43% ACN in H₂O over 26 mins on a Synergi Hydro RP 30×250 m 4 uparticle column (Phenomenex PN 00G-4375-U0-AX) eluted compound 19 (29.5mins) and compound 18 (30.1 mins). Pure fractions were lyophilized toproduce a white powder. Compound 19: ³¹P-NMR (DMSO-d6) 3.448 ppm; MS:m/z: 544 [M−1]⁻; Compound 18: ³¹P-NMR (DMSO-d6) 3.538 ppm; MS: m/z: 544[M−1]⁻.

Example 32

The diastereomers of compound 3 were separated by RP-HPLC. A gradient of25-52% ACN in H₂O over 26 mins on a Synergi Hydro RP 30×250 m 4uparticle column (Phenomenex PN 00G-4375-U0-AX) eluted compound 21 (24.8mins) and compound 20 (25.3 mins). Pure fractions were lyophilized toproduce a white powder. Compound 21: ³¹P-NMR (DMSO-d6) 3.492 ppm; MS:m/z: 584 [M−1]⁻. Compound 20: ³¹P-NMR (DMSO-d6) 3.528 ppm; MS: m/z: 584[M−1]⁻.

Example 33

Compound 2-1 (32 mg, 0.1 mmol) was dissolved in dry THF (3 mL) and 2Msolution of isopropylmagnesium bromide in THF (0.1 mL) was added at 0°C. The reaction was left for 1 h at R.T., andphenyl(isopropyl-L-alaninyl)thiophosphorochloridate was added (0.3mmol). The mixture was left overnight at R.T. LSMS analysis showed about20% of unreacted starting material. The same amount of Grignard reagentand thiophosphorochloridate were added, and the mixture was heated at37° C. for 4 h. The reaction was quenched with NH₄Cl. The product wasextracted with EA, washed with brine, dried over Na₂SO₄, and evaporated.The resulting oil was dissolved in 80% formic acid (4 mL) and in 1 hevaporated. Compound 13 was purified by RP HPLC in gradient of methanolin water from 30% to 95% on Synergy 4u Hydro-RP column (Phenominex)yielding a colorless solid. Compound 13 (7 mg, yield 12.5%). MS: m/z:560.0 [M−1]⁻.

Example 34

Compound 39-1 was synthesized using a procedure similar for preparingcompound 2 using alanine benzyl ester hydrochloride. LCMS: m/z 592[M−1]⁻.

To a solution of 39-1 (1.1 g, 1.85 mmol) in dioxane (15 mL) and water (3mL) was added aqueous triethylammonium acetate (2M, 2 mL, 4 mmol)followed by Pd—C (10%, 100 mg). The mixture was hydrogenated (balloon)for 2 h, and monitored by HPLC. The catalyst was filtered off, and thefiltrate was concentrated to dryness. The residue was suspended in 3%solution of lithium perchlorate in acetone (25 mL). The solid wasisolated by filtration, rinsed with acetone and dried under vacuum togive compound 39 (bis-lithium salt) (731 mg, 90%). LCMS: m/z 426 [M−1]⁻.

Example 35

Compound 1 (40 mg, 0.14 mmol) and triethylammoniumbis(pivaloyloxymethyl)phosphate (0.21 mmol, prepared from 80 mg ofbis(pivaloyloxymethyl)phosphate and 30 μL of Et₃N) were renderedanhydrous by coevaporating with pyridine, followed by toluene. Theevaporated residue was dissolved in anhydrous THF (2 mL) and cooled inan ice-bath. Diisopropylethyl amine (73 μL, 3 eq.), BopCl (71 mg, 2eq.), and 3-nitro-1,2,4-triazole (32 mg, 2 eq.) were added. The mixturewas stirred at 0° C. for 90 mins. The mixture was then diluted withEtOAc, washed with sat. aq. NaHCO₃ and brine, and dried (Na₂SO₄).Purification on silica gel column with CH₂Cl₂/i-PrOH solvent system(4-10% gradient) followed by RP-HPLC purification (A: water, B: MeCN)yielded compound 55 (13 mg, 16%). MS: m/z=1167 [2M−1].

Example 36

Compound 45-1 (15.0 g, 25.55 mmol) was treated with 90% HOAc (150 mL) atR.T. The mixture was stirred at 110° C. for 12 h, and then concentratedat a low pressure. The residue was dissolved in DCM, and the solutionwas washed with brine. The organic phase was dried over anhydrousNa₂SO₄, and then concentrated at a low pressure. The residue waspurified by column chromatography (5% MeOH in DCM) to give 45-2 (11.0 g,88.9%) as a white solid.

Compound 45-2 (12.0 g, 24.79 mmol) was treated with NH₃ in MeOH (200 mL,7 M) at R.T. The solution was stirred at R.T. for 12 h, and thenconcentrated at a low pressure. The residue was purified by columnchromatography (10% MeOH in DCM) to give 45-3 (6.5 g, 95.0%) as a whitesolid.

To a stirred suspension of 45-3 (4.3 g, 15.58 mmol), PPh₃ (8.16 g, 31.15mmol), imidazole (2.11 g, 31.15 mmol) and pyridine (15 mL) in anhydrousTHF (45 mL) was added a solution of I₂ (7.91 g, 31.15 mmol) in THF (100mL) dropwise at 0° C. The mixture was slowly warmed to R.T. and stirredovernight. The mixture was quenched with MeOH (100 mL). The solvent wasremoved at a low pressure, and the residue was re-dissolved in a mixtureof EA and THF (0.2 L, 10:1). The organic phase was washed with sat.Na₂S₂O₃ aq. (2×). The aqueous phase was extracted with a mixture of EAand THF (0.2 L, 10:1, 2×). The concentrated organic phase was dried overanhydrous Na₂SO₄. The residue was purified on a silica gel column (0-10%MeOH in DCM) to afford 45-4 (5.1 g, 85.0%) as a white solid.

Compound 45-4 (800 mg, 2.07 mmol) was dissolved in a mixture of DBU (4mL) and THF (4 mL) at R.T. under N₂. The solution was stirred at R.T.for 1 h. The mixture was neutralized with HOAc, and extracted with amixture of EA and THF (10:1, 40 mL). The organic phase was washed withbrine, and dried over anhydrous Na₂SO₄. The concentrated organic phasewas purified by column chromatography (0-10% MeOH in DCM) to give 45-5(240 mg, 44.9%) as a white solid.

To an ice-cooled solution of 45-5 (1.20 g, 4.65 mmol) in anhydrous MeCN(12 mL) was added NIS (1.57 g, 6.97 mmol) and TEA.3HF (1.12 g, 6.97mmol) under N₂. The mixture was stirred at R.T. for 5 h. The reactionwas quenched with sat. NaHCO₃ solution, and extracted with EA (3×100mL). The organic phase was dried over anhydrous Na₂SO₄, and evaporatedto dryness at low pressure. The residue was purified on a silica gelcolumn (0-5% MeOH in DCM) to give 45-6 (0.91 g, 48.6%) as a white solid.

To a stirred solution of 45-6 (1.2 g, 2.97 mmol) in anhydrous DCM (12mL) was added BzCl (0.83 g, 5.94 mmol), TEA (0.6 g, 5.94 mmol) and DMAP(0.72 g, 5.94 mmol) successively at R.T. The mixture was stirred at R.T.for 12 h. The reaction was quenched with water, and extracted with EA(3×60 mL). The organic phase was concentrated at low pressure. Theresidue was purified by column chromatography (0-5% MeOH in DCM) to give45-7 (1.2 g, 66.2%) as a white solid.

Tetra-butyl ammonium hydroxide (25.78 mL, 51.78 mmol) was neutralizedwith TFA (4.3 mL) to pH=4, and the solution was added to a solution of45-7 (1.09 g, 2.14 mmol) in DCM (30 mL). m-CPBA (1.85 g, 10.74 mmol) wasadded portionwise under vigorous stirring, and the mixture was stirredfor 12 h. The mixture was diluted with EA (100 mL), and washed with sat.sodium bicarbonate. The organic phase was concentrated at low pressure.The residue was purified by column chromatography (50% EA in PE) to give45-8 (350 mg, 41.1%) as a white solid.

Compound 45-8 (280 mg, 0.704 mmol) was treated with NH₃ in MeOH (10 mL,7 M) at R.T. The mixture was stirred at R.T. for 2 h. The mixture wasconcentrated at a low pressure. The residue was purified by columnchromatography (0-10% MeOH in DCM) to give compound 45 (110 mg, 53.1%)as a white solid. ESI-LCMS: m/z 295.1 [M+H]⁺.

Example 37

To an ice-cooled solution of 54-1 (10 g, 42 mmol) in anhydrous MeCN (200mL) was added TEA.3HF (10 g, 62.5 mmol) and NIS (28 g, 126 mmol). Themixture was stirred at R.T. for 1.5 h, and monitored by LCMS. After thereaction was completed, the mixture was concentrated at a low pressure.The residue was purified by silica gel column chromatography (15% MeCNin DCM) to give 54-2 (12 g, 74%) as a yellow solid.

To a solution of 54-2 (22 g, 57 mmol) in anhydrous DCM (200 mL) wasadded DMAP (21 g, 171 mmol) and BzCl (17.6 g, 125 mol). The mixture wasstirred for 5 h at R.T., and monitored by LCMS. The solution was washedwith sat. NaHCO₃ solution, brine and extracted with EA. The organicphase was dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated at low pressure. The residue was purified by silica gelcolumn chromatography (20% EA in PE) to give 54-3 (30 g, 88%) as a whitefoam.

To a solution of 54-3 (6.5 g, 11 mmol) in anhydrous DMF (270 mL) wasadded NaOBz (15.8 g, 110 mmol) and 15-crown-5 (29 g, 132 mmol). Themixture was stirred at 95° C. for 48 h. The precipitate was removed byfiltration, and the organic solvent was removed at low pressure. Theresidue was dissolved in EA (200 mL), and the solution was washed withsat. NaHCO₃ solution, and brine. The organic layer was dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated at lowpressure. The residue was purified by silica gel column chromatography(20% EA in PE) to give 54-4 (3 g crude, 46.1%) as an oil.

Compound 54-4 (3 g, crude) was treated with NH₃ in MeOH (120 mL, 7 M).The mixture was stirred for 3 h and monitored by TLC. The solution wasconcentrated at low pressure. The residue was purified by silica gelcolumn chromatography (10% isopropanol in DCM) to give 54-5 (1.0 g, 67%)as a white solid. ¹H-NMR (CD₃OD, 400 MHz) δ=1.19 (s, 3H), 3.76-3.82 (m,2H), 4.02 (d, J=19.8 Hz, 1H), 5.70 (d, J=8.07 Hz, 1H), 6.27 (s, 1H),7.89 (d, J=8.07 Hz, 1H).

Compound 54-5 (100 mg, 0.36 mmol) was co-evaporated with toluene 3times. To a stirred solution of 54-5 (100 mg, 0.36 mmol) in a mixture ofMeCN (1.0 mL) and NMI (295 mg, 3.6 mmol) was added a solution of 54-C(255.6 mg, 0.72 mmol, preparation described below) in MeCN (0.5 mL) at0° C. The mixture was stirred at R.T. overnight. The reaction wasquenched with water, and diluted with EA (20 mL). The organic layer waswashed with water and brine. The organic layer was dried over anhydrousNa₂SO₄. The organic phase was concentrated at low pressure. The residuewas purified on a silica gel column (5% i-PrOH in DCM) to give the crudeproduct. The product was purified by prep-HPLC (0.1% HCOOH in water andMeCN) to give compound 54 (46.7 mg, 23.3%) as a white solid. ESI-LCMS:m/z 618 [M+Na]⁺.

To a stirred solution of 54-A (2.0 g, 13.16 mmol) and naphthalen-1-ol(1.89 g, 13.16 mmol) in anhydrous DCM (100 mL) was added a solution ofTEA (1.33 g, 13.16 mmol) in DCM (20 mL) dropwise at −78° C. Afteraddition, the mixture was gradually warmed to R.T., and stirred for 2 h.The solution was cooled to −78° C., and (S)-isopropyl 2-aminopropanoatehydrochloride (2.20 g, 13.16 mmol) in DCM (20 mL) was added, followed byTEA (2.66 g, 26.29 mmol) in DCM (20 mL) dropwise. The mixture wasgradually warmed to R.T., and stirred for 2 h. The organic solvent wasremoved at low pressure. The residue was dissolved in methyl-butylether. The precipitate was filtered, and the filtrate was concentratedat low pressure. The residue was purified on a silica gel column(anhydrous DCM) to give 54-C (1.0 g, 24.8%) as a colorless oil.

Example 38

To a solution of 54-5 (300 mg, 1.08 mmol) and NMI (892 mg, 10 mmol) inanhydrous MeCN (4 mL) was added a solution of 57-C (736 mg, 2.17 mmol,preparation described below) in anhydrous MeCN (1 mL) dropwise at 0° C.The mixture was stirred at R.T. overnight. The reaction was quenchedwith water, and diluted with EA (30 mL). The organic layer was washedwith water and brine. The organic phase was dried over anhydrous Na₂SO₄and concentrated at low pressure. The residue was purified by a silicagel column (iPrOH in DCM from 1% to 5%) to give crude compound 56 (276mg, crude). Crude compound 56 (96 mg) was purified by prep-HPLC (0.1%HCOOH in water and MeCN) to give pure compound 56 (46 mg, 47.9%) as awhite solid. ESI-LCMS: m/z 560 [M−F]⁺.

To a solution of compound 56 (180 mg, 0.31 mmol) in anhydrous pyridine(6 mL) was added acetic anhydride (158 mg, 1.54 mmol) dropwise at 0° C.The mixture was stirred at R.T. overnight. The solution was quenchedwith water and concentrated at a low pressure. The residue was dissolvedin EA (10 mL), and washed with brine. The organic layer was dried overanhydrous Na₂SO₄. The organic phase was concentrated at low pressure.The residue was purified by silica gel column (i-PrOH in DCM from 1% to3%) to give crude compound 57 (172 mg). Crude compound 57 was purifiedby prep-HPLC (0.1% HCOOH in water and MeCN) to give pure compound 57 (46mg, 23.8%) as a white solid. ESI-LCMS: m/z 602.3 [M−F]⁺.

Compound 56-C (1.02 g, 23%, a colorless oil) was prepared using aprocedure similar to the preparation of 54-C using 54-A (2.00 g, 13.16mmol) and 4-chlorophenol (1.68 g, 13.16 mmol).

Example 39

Compound 25 (109 mg, 0.39 mmol) and triethylammoniumbis(isopropyloxycarbonyloxymethyl)phosphate (0.6 mmol, prepared from 195mg of bis(isopropyloxycarbonyloxymethyl)phosphate and 85 μL of Et₃N)were rendered anhydrous by coevaporating with pyridine, followed bytoluene. The residue was dissolved in anhydrous THF (3 mL) and cooled inan ice-bath. Diisopropylethyl amine (0.2 mL, 3 eq.), BopCl (190 mg, 2eq.), and 3-nitro-1,2,4-triazole (81 mg, 2 eq.) were added, and themixture was stirred at 0° C. for 90 mins. The mixture was diluted withEtOAc, washed with sat. aq. NaHCO₃ and brine, and dried (Na₂SO₄).Purification on silica gel column with CH₂Cl₂/i-PrOH (4-10% gradient)followed by RP-HPLC purification (A: 0.1% HCOOH in water, B: 0.1% HCOOHin MeCN) yielded compound 61 (28 mg, 12%). ¹H-NMR (CDCl₃): δ 7.24 (d,1H), 6.6 (br, 1H), 5.84 (d, 1H), 5.65-5.73 (m, 4H), 4.94 (m, 2H), 4.38(m, 2H), 4.1 (b, 1H), 2.88 (d, 1H), 1.47 (d, 3H), 1.33 (m, 12H).

Example 40

Dry nucleoside (0.05 mmol) was dissolved in a mixture of PO(OMe)₃ (0.7mL) and pyridine (0.3 mL). The mixture was evaporated in vacuum for 15mins. at 42° C., then cooled to R.T. N-Methylimidazole (0.009 mL, 0.11mmol) was added followed by POCl₃ (0.009 mL, 0.11 mmol). The mixture waskept at R.T. for 20-40 mins and monitored for the formation of compound74 by LCMS. The reaction was quenched with water and isolated by RP HPLCon Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient ofmethanol from 0 to 30% in 50 mM triethylammonium acetate buffer (pH 7.5)was used for elution. The corresponding fractions were combined,concentrated and lyophilized 3 times to remove excess of buffer. MS: m/z396.5 [M−1]⁻.

Example 41

The nucleoside (140 mg, 0.42 mmol) was dissolved in n-butylamine (0.5mL). The mixture was kept for 2 h at R.T., and the amine was thenevaporated. The residue was dissolved in EtOAc, and the organic layerwas washed twice with 10% citric acid, dried over Na₂SO₄, andevaporated. The residue purified by column chromatography on silica gelin linear gradient of methanol in DCM from 0% to 12% over 10 columnvolumes. The fractions containing the product were concentrated andtreated with 80% HCOOH for 1 h at R.T. The mixture was evaporated todryness, and suspended in CH₃CN. The precipitate was separated, washedwith CH₃CN (1 mL) and dried to yield compound 68 (27 mg, 50%). MS: m/z326.5 [M−]⁻.

Example 42

Compound 45 (30 mg, 0.1 mmol) was dissolved in a mixture of CH₃CN (2 mL)and N-methylimidazole (200 uL). Phosphorochloridate (100 mg, 0.3 mmol)was added, and the mixture was kept for 5 d at R.T. The mixture wasdistributed between water and EA. The organic layer was separated,washed with brine, dried and evaporated. The phosphoroamidate wasisolated by silica gel chromatography in a gradient of methanol in DCMfrom 3% to 10%. The corresponding fractions were concentrated andre-purified by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex).A linear gradient of methanol in DCM from 3% to 95% containing 0.1%formic acid was used for elution. Compound 62 was obtained as a mixtureRp and Rs isomers (9 mg, 16%). MS: m/z 562.1 [M−1]⁻.

Example 43

Compound 47 (30 mg, 0.1 mmol) was dissolved in a mixture of CH₃CN (2 mL)and N-methylimidazole (200 uL). Phosphorochloridate (100 mg, 0.3 mmol)was added, and the mixture was kept overnight at 40° C. The temperaturewas increased to 65° C. and heated for 1 h. The mixture was distributedbetween water and EA. The organic layer was separated, washed withbrine, dried and evaporated. The azido-phosphoramidate was purified byRP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A lineargradient of methanol from 30% to 100% in 50 mM triethylammonium acetatebuffer (pH 7.5) was used for elution. The azido-phosphoramidate (8 mg)was dissolved in pyridine/Et₃N (3 mL, 8:1 v/v) and cooled to 0° C. H₂5gas was bubbled through the solution for 10 min, and the reaction waskept for 1 h at R.T. The solvents were evaporated, and the residueisolated by RP HPLC. The corresponding fractions were combined,concentrated and lyophilized 3 times to remove excess of buffer, toprovide compound 72 (1.2 mg) as mixture Rp and Rs isomers. MS: m/z 544.1[M+1]⁺.

Example 44

To a solution of 65-1 (23.0 g, 39.5 mmol) in anhydrous toluene (200 mL)was added DAST (31.9 g, 198 mmol) dropwise at −78° C., and the solutionwas stirred at −78° C. for 3 h. The mixture was quenched with sat.NaHCO₃, extracted with EA (2×200 mL) and dried over with anhydrousNa₂SO₄. The solution was concentrated to dryness under low pressure. Theresidue was purified on a silica gel column (50% EA in PE) to give 65-2(16.5 g, 71%) as a yellow foam.

A mixture of 65-2 (16.0 g, 27.4 mmol) and NH₄F (3.0 g, 82.2 mmol) inmethanol (100 mL) was stirred at 70° C. for 12 h. The reaction wascooled, and the salt was removed by filtration. The filtrate wasconcentrated to dryness at low pressure. The residue was purified on asilica gel column (3% MeOH in DCM) to give 65-3 (5.1 g, 69.0%) as awhite foam.

To a stirred suspension of 65-3 (4.1 g, 15.2 mmol), PPh₃ (8.0 g, 30.4mmol), imidazole (2.1 g, 30.4 mmol) and pyridine (18.2 mL) in anhydrousTHF (40 mL) was added dropwise a solution of I₂ (5.8 g, 22.8 mmol) inTHF (20 mL) at 0° C. The mixture was stirred at R.T. for 12 h. Thereaction was quenched with MeOH (100 mL), and the solvent was removedunder reduced pressure. The residue was purified on a silica gel column(4% MeOH in DCM) to give pure 65-4 (4.4 g, 77%) as a white solid.ESI-MS: m/z 381.1 [M+1]⁺.

To a stirred solution of 65-4 (2.5 g, 0.7 mmol) in anhydrous THF (3 mL)was added DBU (2.1 g, 14 mmol) at R.T., and the mixture was stirred atR.T. for 1 h. The reaction was quenched with HOAc, and diluted with2-Me-tetrahydrofuran. The solution was washed with brine, dried overwith anhydrous Na₂SO₄ and concentrated to dryness at low pressure. Theresidue was purified on a silica gel column (MeOH 5% in DCM) to give65-5 (1.1 g, 68.9%) as a white foam.

To a stirred solution of 65-5 (800 mg, 3.17 mmol) in anhydrous CH₃CN (10mL) was added TEA.3HF (510 mg, 3.17 mmol) and NIS (785 mg, 3.49 mmol) at0° C. The mixture was stirred for 30 mins, gradually warmed to R.T., andstirred for 1 h. The mixture was quenched with sat. NaHCO₃ solution andNa₂S₂O₃ solution, and extracted with EA (2×20 mL). The organic layer wasdried over with anhydrous Na₂SO₄, and concentrated to dryness at lowpressure. The residue was purified on a silica gel column to give pure65-6 (695 mg, 57.9%) as a yellow solid.

To a stirred solution of 65-6 (650 mg, 1.63 mmol) in pyridine (3 mL) wasadded BzCl (507 mg, 3.59 mmol) at 0° C., and stirred at R.T. for 12 h.The mixture was quenched with water, and concentrated to dryness underreducing pressure. The residue was purified on a silica gel column (EA50% in PE) to yield 65-7 (550 mg, 67%) as a white foam.

Tetra-butylammonium hydroxide (9 mL as 54-56% aqueous solution, 72 mmol)was neutralized with TFA to pH-4 (1.5 mL), and the mixture was added toa solution of 65-7 (375 mg, 0.75 mmol) in DCM (9 mL). m-Chloroperbenzoicacid (924 mg, 60-70%, 3.75 mmol) was added in portions with vigorousstirring, and the mixture was stirred overnight. The mixture was washedwith brine, dried over magnesium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography (EA 50% inPE) to give 65-8 (230 mg, 78.8%) as a white foam. ESI-MS: m/z 393.1[M+1]⁺.

Compound 65-8 (120 mg, 0.24 mmol) was treated with 7N NH₃.MeOH (20 mL),and stirred for 5 h. The mixture was concentrated to dryness at lowpressure. The residue was purified on a silica gel column (propan-2-ol15% in DCM) to yield compound 65 (53 mg, 60.2%) as a white solid.ESI-MS: m/z 288.8 [M+1]⁺.

Example 45

To a solution of 70-1 (3.0 g, 18.0 mmol) and POCl₃ (1.35 g, 9.0 mmol) inDCM (80 mL) was added TEA (3.6 g, 36.0 mmol) in DCM (20 mL) dropwise at0° C. The mixture was stirred at 0° C. for 2 h. A solution ofpentafluorophenol (1.65 g, 9.0 mmol) and TEA (0.9 g, 9.0 mmol) in DCM(20 mL) was added dropwise at 0° C., and the mixture was stirred at 0°C. for 15 h. After the reaction was completed, the mixture wasconcentrated under reduced pressure. The residue was washed by TBME andfiltered. The filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel chromatography (20% EA in PE) to give70-2 (2.7 g, 62.7%) as a white solid. ESI-MS: m/z 491.1 [M+1]⁺.

To a stirred solution of1-((3aR,4R,6S,6aS)-6-fluoro-6-(hydroxymethyl)-2-methoxy-3a-methyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-dione (150 mg, 0.47 mmol) in anhydrous THF (2 mL) was added asolution of t-BuMgCl (0.46 mL, 1M in THF) dropwise at 0° C. The mixturewas stirred at R.T. for 40 mins, and re-cooled to 0° C. A solution of70-2 (462 mg, 0.94 mmol) was added, and the mixture was stirred at R.T.for 4 h. The mixture was quenched with H₂O, and extracted with EA. Theorganic layer was dried over Na₂SO₄ and concentrated under reducingpressure. The residue was purified on a silica gel column (50% EA in PE)to give 70-3 as a white foam (230 mg, 78%).

Compound 70-3 (230 mg, 0.37 mmol) was dissolved in 80% HCOOH aqueoussolution (20 mL), and the mixture was stirred at R.T. for 24 h. Thesolvent was removed at low pressure. The residue was purified on asilica gel column to give the crude product, which was purified by RPHPLC (HCOOH system) to give compound 70 as a mixture of two P-isomers(75 mg, 33%). ESI-TOF-MS: m/z 583.0 [M+H]⁺.

Example 46

To a solution of 75-1 (120 g, 0.26 mol) in CH₃CN (2.0 L) was added IBX(109 g, 0.39 mol), and refluxed for 12 h. The reaction was monitored byTLC and LCMS. After cooling to R.T., the mixture was filtered, and thefiltrate was concentrated at low pressure. The crude product was useddirectly for the next step.

Compound 75-2 (130 g, 0.26 mol) was co-evaporated with anhydrous toluenethree times to remove H₂O. To a solution of 75-2 in THF (300 mL) wasadded dropwise vinyl magnesium bromide (700 mL, 0.78 mol, 1N in THF)over 30 min at −78° C. The mixture was stirred for about 1 h at R.T.After the starting material was consumed, the mixture was poured into asat. NH₄Cl solution. The organic layer was washed with brine, dried withanhydrous Na₂SO₄ and filtered. The solution was concentrated at lowpressure to get the crude product. To a solution of this crude product(170 g, 0.346 mol) in anhydrous CH₂Cl₂ was added TEA (105 g, 1.04 mol)and DMAP (84 g, 0.69 mol). Benzoyl chloride (146 g, 1.04 mol) was addedslowly at R.T. for 12 h. The mixture was diluted with CH₂Cl₂ and thenwashed with sat. aq. NaHCO₃. The combined aq. phase was extracted withDCM (100 mL), and the combined organic phase was dried with Na₂SO₄.After filtration, the solution was evaporated to dryness under reducedpressure, and the residue was purified by column chromatography to give75-3 (107 g, 52%).

Uracil (44.8 g, 0.4 mol) (co-evaporated with toluene twice) and NOBSA(81.4 g, 0.4 mol) were dissolved in CH₃CN (500 mL). The mixture wasrefluxed for 1.5 h and then slowly cooled to R.T. The mixture wastreated with 75-3 (59 g, 0.1 mol) and TMSOTf (155 g, 0.7 mol), and thenwarmed to 60-70° C. for 12 h. The mixture was neutralized with a sat.NaHCO₃ solution, and extracted with EA (3×1000 mL). The solution wasdried over anhydrous MgSO4, and evaporated at low pressure. The residuewas purified using a silica gel column to give pure 75-4 (40 g, 69%) asa white solid.

To a solution of 75-4 (50 g, 0.086 mol) in DMF was added PMBCl (16 g,0.1 mol) and K₂CO₃ (17.8 g, 0.13 mol) at 0° C., and the mixture wasstirred at R.T. for 12 h. The mixture was quenched with water (100 mL),and extracted with EA (3×200 mL). The organic phase was concentrated atlow pressure to give crude 75-5 (65 g) which was used in the next stepwithout further purification.

To a solution of crude 75-5 (65 g, 0.086 mol) in MeOH/DCM (4/1) (200 mL)was added NaOMe (16.8 g, 0.3 mol), and the mixture was stirred at R.T.for 2.5 h. The reaction was quenched with dry ice, and then concentratedat low pressure. The residue was dissolved in EA (200 mL) and washedwith brine. The organic layer was concentrated at low pressure, and theresidue was purified using a silica gel column using 1% MeOH in CH₂Cl₂to give 75-6 as a yellow foam (25 g, 75%).

To a solution of 75-6 (25.5 g, 0.065 mol) in DMF was added NaH (10.5 g,0.26 mol) slowly at 0° C., and the mixture was stirred for 30 mins. BnBr(36.3 g, 0.21 mol) was added, and the mixture was stirred at R.T. for 12h. The reaction was quenched with sat. NH₄Cl (aq.), and then extractedwith EA (3×100 mL). The solution was dried over anhydrous MgSO₄, andevaporated at low pressure. The residue was purified by a silica gelcolumn using 10% EA in PE to give 75-7 (20 g, 46%) as a white solid.

To a solution of 75-7 (20 g, 0.03 mol) and NMMO (7 g, 0.06 mol) inTHF:H₂O (5:1) (100 mL) was added OsO₄ (2.6 g, 0.01 mol) at R.T., and themixture was stirred at R.T. for 24 h. The mixture was quenched with asat. Na₂S₂O₃ solution, and extracted with EA (3×100 mL). The organiclayer was washed with brine, and dried over anhydrous MgSO₄. Thesolution was evaporated at low pressure to give the crude compound,which was used in the next step without further purification.

To a solution of the crude diol (0.03 mol) in MeOH:H₂O:THF (170 mL:30mL:50 mL) was added NaIO₄ (9.6 g, 0.045 mol), and the mixture wasstirred at R.T. for 2 h. After filtration, the filtrate was useddirectly in the next step. This solution was treated with NaBH₄ (1.8 g,0.048 mol) at 0° C., and the mixture was stirred at R.T. for 30 mins.The mixture was quenched with MeOH, and evaporated at low pressure. Theresidue was dissolved in EA (100 mL), and washed with brine. Thesolution was evaporated at low pressure, and the residue was purified bya silica gel column using 20% EA in EA to give 75-8 (12 g, 61% overthree steps).

To a solution of 75-8 (14 g, 21 mmol) and DMAP (5.1 g, 42 mmol) in DCM(100 mL) was added MsCl (3.1 g, 27 mmol) at 0° C., and the mixture wasstirred at R.T. for 40 mins. The reaction was quenched with sat. NaHCO₃(aq.), and washed with HCl (0.2 N) solution. The organic phase was driedover anhydrous MgSO₄, and evaporated at low pressure. The residue waspurified by a silica gel column using 5% EA in PE to give mysolateproduct (14 g, 90%). The MsO-product (41 g, 55 mmol) was treated withTBAF (1 N in THF, 500 mL), and the mixture was stirred at 70-80° C. for3 d. The mixture was concentrated at low pressure, and the residue wasdissolved in EA (200 mL). The solution was washed with brine, dried overanhydrous MgSO₄ and evaporated at low pressure. The residue was purifiedby chromatography using 10% EA in PE to give 75-9 (9.9 g, 27%).

To a solution of 75-9 (6.3 g, 9.45 mmol) in CH₃CN:H₂O (3:1, 36 mL:12 mL)was added CAN (15.5 g, 28.3 mmol), and the mixture was stirred at R.T.overnight. The mixture was extracted with EA (3×50 mL). The solution wasdried over anhydrous MgSO₄, and evaporated at low pressure. The residuewas purified by chromatography using 20% EA in PE to give 75-10 (3.6 g,71%) as a white solid.

To a solution of 75-10 (2.4 g, 4.4 mmol) in anhydrous DCM (10 mL) wasadded slowly BCl₃ (1 N, 30 mL CH₂Cl₂) at −70° C., and the mixture wasstirred for 2 h. at −70° C. The mixture was quenched with the slowaddition of MeOH at −70° C., and the mixture was concentrated at lowpressure. The residue was purified by chromatography using 50% EA in PEto give 75-11 (1.2 g, 86%) as a white solid. ESI-MS: m/z 277.1 [M+H]⁺.

To a solution of PPh₃ (3.37 g, 12.8 mmol) in pyridine (15 mL) was addedI₂ (3.06 g, 12 mmol) at 0° C., and the mixture was stirred at R.T. for30-40 mins. The mixture was cooled to 0° C., and then treated with 75-11(2.2 g, 8 mmol) in Py. (5 mL). The mixture was stirred at R.T. under N₂for 12 h. The mixture was quenched with sat. Na₂S₂O₃ (aq.) and extractedwith CH₂Cl₂ (3×50 mL). The organic phase was dried over anhydrous MgSO₄,and then concentrated at low pressure. The residue was purified bychromatography using 1-2% MeOH in CH₂Cl₂ to yield 75-12 (1.8 g, 58%) asa white solid.

To a solution of 75-12 (1.35 g, 3.5 mmol) in THF:CH₃CN (10 mL:5 mL) wasadded DBU (1.06 g, 7 mmol), and the mixture was stirred at 60-70° C. for2 h. The mixture was concentrated at low pressure, and the residue wasdissolved in EA (20 mL). The solution was washed with 10% HCl solutionand brine. The organic phase was dried over anhydrous MgSO₄ andconcentrated at low pressure. The residue was purified by chromatographyusing 30% EA in PE to give 75-13 (0.5 g, 55%).

To a solution of 75-13 (670 mg, 2.6 mmol) in CH₃CN (6 mL) was added NIS(730 mg, 3.25 mmol) and 3HF.TEA (335 mg, 2.1 mmol) at 0° C., and themixture was stirred at R.T. for 2 h. The mixture was quenched with sat.NaHCO₃ (aq.) and Na₂S₂O₃ (aq.) solution. The mixture was extracted withEA (3×20 mL), dried over anhydrous MgSO₄ and concentrated at lowpressure. The residue was purified by chromatography using 1-2% MeOH inCH₂Cl₂ to give 75-14 (1.2 g, 80%).

To a solution of 75-14 (1.0 g, 2.47 mmol), DMAP (0.75 g, 6.2 mmol) andTEA (0.75 g, 7.42 mmol) in DCM (10 mL) was added BzCl (1.15 g, 8.16mmol) in DCM (1 mL) at 0° C., and the mixture was stirred at R.T. for 12h. The mixture was diluted with CH₂Cl₂ (10 mL), and then washed with HCl(0.1 N, 20 mL) solution and brine. The organic phase was dried overanhydrous MgSO₄, and concentrated at low pressure. The residue waspurified by chromatography using 20% EA in PE to afford 75-15 (850 mg,purity˜80%).

To a solution of 75-15 (600 mg, 1 mmol) in DMF (25 mL) was added BzONa(1.45 g, 10 mmol), 15-crown-5 (2.2 g, 10 mmol), and the mixture wasstirred at 90-100° C. for 24 h. The mixture was concentrated at lowpressure, and the residue was dissolved in EA (20 mL), and washed withbrine. The organic phase was dried over anhydrous MgSO₄, and thenconcentrated at low pressure. The residue was purified by chromatographyusing 15% EA in PE to give 75-16 (275 mg, 37%) as a light yellow foam.

Compound 75-16 (250 mg, 0.41 mmol) was treated with NH₃.MeOH (7 N, 5mL), and the mixture stirred at R.T. for 15 h. The mixture wasconcentrated at low pressure, and the residue was purified by prep-HPLCto give compound 75 (33 mg, 25%) as a white solid. ESI-MS: m/z 295.1[M+H]⁺.

Example 47

To a solution of IBX (133.33 g, 476 mmol) in dry CH₃CN (2 L) was added73-1 (100.0 g, 216 mol) at R.T. The mixture was refluxed and stirred for12 h. The mixture was filtered, and the filtrate was concentrated at lowpressure to give 73-2 as a yellow oil (90.0 g, 90.4%).

Compound 73-2 (50.0 g, 108.70 mmol) was coevaporated with anhydroustoluene twice to remove H₂O. Ethynyl magnesium bromide, (800 mL, 400.0mmol) was added dropwise into a solution of 73-2 in THF (500 mL) over 20mins at −78° C. The mixture was stirred for about 10 mins at −78° C.When the starting material was consumed, the ice-acetone cooling bathwas removed. The mixture was quenched with a sat. NH₄Cl solution withstirring, and then warmed to R.T. The mixture was extracted with EA,filtered through Celite and washed with brine. The combined organicphase was dried over anhydrous Na₂SO₄, filtered and concentrated at lowpressure to give crude 73-3 as a deep yellow oil (48.0 g, yield: 90.8%).

Compound 73-3 (200.0 g, 411.52 mmol) was dissolved in anhydrous CH₂Cl₂(2000 mL) and then DMAP (100.41 g, 823.05 mmol) and Et₃N (124.94 g, 1.23mol) were added at R.T. The mixture was treated with benzoyl chloride(173.46 g, 1.23 mol) at 0° C. After stirring for 12 h at R.T., thereaction was quenched with H₂O. The combined aq. phase was extractedwith DCM. The combined organic phase was dried over anhydrous Na₂SO₄,filtered and evaporated to dryness under reduced pressure to give ablack oil. The oil was purified by column chromatography using 7%-20% EAin PE as the eluent to give a yellow oil. The residue triturated withCH₃OH and filtered. The filter cake was concentrated in vacuo to give73-4 as a white solid (30.0 g, 36.4%).

Uracil (34.17 g, 305.08 mmol) were coevaporated with anhydrous toluenetwice to remove H₂O. To a stirred suspension of uracil in anhydrous MeCN(150 mL) was added N,O-BSA (123.86 g, 610.17 mmol) at R.T. The mixturewas refluxed for 1.5 h and then cooled to R.T. Compound 73-4 (90 g,152.54 mmol, which were coevaporated with anhydrous toluene twice toremove H₂O) was added. TMSOTf (237.05 g, 1.07 mol) was then added atR.T. The mixture was heated to 70° C., and then stirred overnight andthen monitored by LCMS. The mixture was cooled to R.T., and quenchedwith a sat. NaHCO₃ solution. The solution was extracted with EA. Theorganic layer was dried over Na₂SO₄, and then concentrated at lowpressure. The residue was purified using a silica gel column eluted with10%-50% EA in PE to give 73-5 as a white solid (45 g, 50.9%).

Compound 73-5 (50 g, 86.21 mmol) was treated with NH₃ in MeOH (1 L) atR.T., and then stirred for 48 h. The mixture was concentrated at lowpressure, and the residue was purified by column chromatography (10%MeOH in DCM) to give 73-6 (12.6 g, 54.55%) as a white solid.

To a solution of cyclopentanone (100 g, 1.189 mmol) and trimethylorthoformate (150 mL) in MeOH (600 mL) was added TsOH.H₂O (1.13 g, 5.9mmol), and the mixture was stirred at R.T. for 30 mins. The reaction wasquenched with NaOMe (0.32 g, 5.9 mmol) and H₂O, and the solution wasextracted by n-hexane. The organic layer was dried over anhydrousNa₂SO₄, and then concentrated at low pressure. The cyclopentyl dimethoxyacetal and 73-6 (20 g, 74.63 mmol) was dissolved in DCE (200 mL), andthen treated with TsOH.H₂O (0.71 g, 3.73 mmol). The mixture was stirredat 50° C. for 12 h, and then concentrated at low pressure. The residuewas purified by silica gel column chromatography (1-10% MeOH in DCM) togive 73-7 (15.4 g, 61.8%) as a white solid.

Compound 73-7 (20.0 g, 0.06 mol) was coevaporated with anhydrouspyridine three times to remove H₂O. To an ice-cold solution of 73-7 inanhydrous pyridine (100 ml) was added TsCl (22.8 g, 0.12 mol) at 0° C.,and the mixture was stirred overnight and monitored by LCMS and TLC. Thereaction was quenched with H₂O and extracted with EA. The organic phasewas dried over anhydrous NaSO₄ and evaporated at low pressure. Theresidue was purified by silica gel column chromatography (DCM:MeOH=100:1 to 15:1) to give 78-8 (20.0 g, 69.0%) as a white solid.

To a solution of 73-8 (20.0 g, 0.04 mol) in acetone (200 ml) was addedNaI (31.0 g, 0.2 mol) and heated to reflux overnight and monitored byLCMS. The mixture was quenched with a sat. Na₂S₂O₃ solution, andextracted with EA. The organic phase was dried over anhydrous Na₂SO₄ andevaporated at low pressure. The residue was purified by silica gelcolumn chromatography (DCM: MeOH=100:1 to 15:1) to give 73-9 (15.0 g,83.3%) as a white solid.

To 73-9 (30.0 g, 0.068 mol) in dioxane (60 mL) in sealed tube was addedCuBr (4.9 g, 0.034 mol), i-Pr₂NH (13.6 g, 0.135 mol) and (CH₂O)_(n)(5.1g, 0.17 mol) under N₂. The mixture was heated at reflux for 16 h. Themixture was diluted with EtOAc, and washed with a sat. NH₄Cl solutionand brine. The solution was dried over anhydrous MgSO₄, and concentratedunder reduced pressure. The residue was purified by columnchromatography (DCM: MeOH=100:1 to 15:1) to give 73-10 (10.0 g, 32.3%)as a white solid.

Compound 73-10 (10 g, 21.83 mmol) was treated with HCOOH (80%) in H₂O atR.T. The solution was stirred at 60° C. for 2 h, and then concentratedat a low pressure. The residue was purified by column chromatography(1%-10% MeOH in DCM) to give 73-11 (5.1 g, 58.55%) as a white solid.

Compound 73-11 (5 g, 12.79 mmol) was dissolved in anhydrous MeOH (100mL) and treated with NaOMe (4.83 g, 89.5 mmol) at R.T. The solution wasstirred at 60° C. for 36 h. The mixture was quenched with CO₂ and thenconcentrated at low pressure. The residue was purified by columnchromatography (0-10% MeOH in DCM) to give 73-12 (2.3 g, 68.05%) as ayellow solid. ¹H-NMR (CDCl₃, 400 MHz) 6=7.29 (d, J=8 Hz 1H), 6.10 (s,1H), 5.71 (d, J=8.0 Hz 1H), 5.18 (t, J=6.4 Hz, 1H), 4.79-4.84 (m, 1H),4.61 (d, J=8.0 Hz, 2H), 4.39 (s, 1H), 3.45 (s, 1H).

To an ice-cold solution of 73-12 (1.5 g, 5.68 mmol) in anhydrous MeCN(15 mL) was added NIS (1.66 g, 7.39 mmol) and TEA.3HF (0.73 g, 4.55mmol) under N₂. The mixture was stirred at R.T. for 1 h. The reactionwas quenched with sat. NaHCO₃ and sat. Na₂SO₃ solution, and extractedwith EA (3×100 mL). The organic phase was dried over anhydrous Na₂SO₄,and evaporated to dryness at low pressure. The residue was purified on asilica gel column (0-5% MeOH in DCM) to give 73-13 (1.08 g, 46.2%) as ayellow solid.

To a stirred solution of 73-13 (1 g, 2.44 mmol) in anhydrous DCM (10 mL)was added DMAP (0.60 g, 4.88 mmol) and Et₃N (0.74 g, 7.32 mmol) at R.T.The mixture was treated with benzoyl chloride (0.79 g, 5.61 mmol) at 0°C. and then stirred at R.T. for 3 h. The reaction was quenched withwater, and extracted with EA (3×60 mL). The organic phase wasconcentrated at low pressure, and the residue was purified by columnchromatography (0-10% MeOH in DCM) to give 73-14 (0.9 g, 59.6%) as awhite solid.

Bu₄NOH (55% in H₂O, 13.74 mL) was treated with TFA (to adjust pH=3-4).The mixture was cooled to R.T. To a solution of 73-14 (0.9 g, 1.46 mmol)in DCM (9 mL) was added m-CPBA (80%, 1.57 g, 7.28 mmol) at R.T. Themixture was stirred at 25° C. for 48 h. The mixture was washed with sat.aq. NaHCO₃. The organic layer was passed through an anhydrous Al₂O₃column, and the solution was concentrated at low pressure. The residuewas purified by a silica gel column (30% EA in PE) to give 73-15 (0.26g, 35.1%) as a yellow solid.

Compound 73-15 (0.25 g, 0.49 mmol) was dissolved in NH₃/MeOH (5 mL, 7M), and the mixture was stirred at R.T. for 24 h under N₂. The mixturewas concentrated at low pressure at R.T., and the residue was purifiedby a silica gel column (5% MeOH in DCM) to give 73-16 (100 g, 67.75%) asa white solid. ¹H-NMR (CD₃OD, 400 MHz) δ=7.83 (d, J=8 Hz 1H), 6.29 (s,1H), 5.67 (d, J=6.0 Hz 1H), 5.12 (t, J=6.8 Hz, 1H), 4.99-5.01 (m, 1H),4.38 (d, J=19.6 Hz 1H), 3.74-3.81 (m, 2H), 3.35 (s, 1H).

Compound 73-16 (100 mg, 0.33 mmol) was co-evaporated with toluene threetimes to remove H₂O. To a stirred solution of 73-16 (100 mg, 0.33 mmol)in a mixture of MeCN (1.0 mL) and NMI (271 mg, 3.3 mmol) was added asolution of 73-C (216.5 mg, 0.66 mmol) in MeCN (0.5 mL) at 0° C. Themixture was stirred at R.T. overnight and then reaction was quenchedwith water. The mixture was diluted with EA (20 mL), and the organiclayer was washed with water and brine, and dried over anhydrous Na₂SO₄.The organic phase was concentrated at low pressure, and the residue waspurified on a silica gel column (5% i-PrOH in DCM) to give the crudeproduct. The crude product was purified by prep-HPLC (0.1% HCOOH inwater and MeCN) to give compound 73 (35.6 mg, 19.0%) as a white solid.ESI-LCMS: m/z 592 [M+Na]⁺.

To a stirred solution of 73-A (2.0 g, 13.16 mmol) and phenol (1.22 g,13.16 mmol) in anhydrous DCM (100 mL) was added a solution of TEA (1.33g, 13.16 mmol) in DCM (20 mL) dropwise at −78° C. The mixture was warmedgradually to R.T., and then stirred for 2 h. The solution was re-cooledto −78° C., and (S)-isopropyl 2-aminopropanoate hydrochloride (2.20 g,13.16 mmol) in DCM (20 mL) was added, followed by the dropwise additionof TEA (2.66 g, 26.29 mmol) in DCM (20 mL). The mixture was warmedgradually to R.T., and then stirred for 2 h. The organic solvent wasremoved at low pressure, and the residue was dissolved in methyl-butylether. The precipitate was filtered, and the filtrate was concentratedat low pressure. The residue was purified on a silica gel column(anhydrous DCM) to give 73-C (0.9 g, 22.3%) as a colorless oil.

Example 48

Compound 66-2 (2648 g, 7.3 mol) was dissolved in anhydrousdichloromethane (10 L), and the solution was cooled to −40° C. withstirring under N₂. Compound 66-1 (1 kg, 7.69 mol) was dissolved inanhydrous CH₂Cl₂ (3 L) and added to the solution of 66-2 over 30 mins at−40° C. The stirred mixture was allowed to warm to R.T. overnight. Themixture was concentrated under reduced pressure to dryness, and theresidue was suspended in TMBE (6 L). The suspension was filtered toremove Ph₃PO, and the filtrate was concentrated under reduced pressureto afford crude 66-3 (1230 g, 78.6%). ¹H NMR (400 Hz) (CDCl₃): δ 6.65(dt, J=7.6 Hz, 1H), 4.82 (dd, J=14.8, 7.6 Hz, 1H), 4.20-4.10 (m, 3H),3.59 (t, J=8.0 Hz, 1H), 1.86 (d, J=1.2 Hz, 3H), 1.41 (s, 3H), 1.37 (s,3H), 1.26 (t, J=6.8 Hz, 3H).

Crude 66-3 (1230 g, 5.74 mol) was dissolved in acetone (30 L) at 0-5° C.KMnO₄ (1107 g, 5.17 mol) was added in one portion. After being stirredat 0-5° C. for 5 h, the reaction was quenched with sat. aq. sodiumsulfite (20 L). After 30 mins, a colorless suspension was formed. Thesolid was removed by filtration and washed with EA (6 L). The filtratewas extracted with EA (3×2 L). The combined extracts were dried overNa₂SO₄, filtered, and concentrated under reduced pressure to give awhite solid residue. The residue was dissolved in EA, and PE was addedto give a precipitate. The solid was collected by filtration andrecrystallization was 3 times to give 66-4 (770 g, 53.6%) as a whitesolid.

To a stirred solution of 66-4 (770 g, 3.1 mol) in anhydrous DCM (5 L)and triethylamine (1.1 L, 8.05 mol) at 0° C. was added slowly sulfurylchloride (300 mL, 3.6 mmol). The mixture was stirred at R.T. for 2 h,diluted with DCM (3 L), and washed with sat. NaHCO₃ aq. and brine. Theorganic phase was dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by asilica gel column using PE:EA=1:0 to 10:1 as the eluent to give 66-5(490 g, 50.6%) as an oil.

Tetraethylammonium fluoride hydrate (650 g, 3.7 mol) was added into asolution of 66-5 (490 g, 1.6 mol) in anhydrous dioxane (3 L), and themixture was heated to 120° C. for 16 h. The mixture was then cooled toambient temperature. 2,2-Dimethoxypropane (3 L) was added followed byconc. aq hydrochloric acid (200 mL). The mixture was stirred for 3 h atambient temperature. The solvent was concentrated to 1/4 of the originalvolume, and then diluted with EA (3 L). The mixture was washed with coldsat. aq. sodium bicarbonate and brine. The combined aqueous layer wasback-extracted with EA (1 L). The combined organic layer was dried overanhydrous Na₂SO₄, filtered, and concentrated at low pressure to givecrude 66-6 (220 g, 70.8%).

Crude 66-6 (220 g, 0.89 mol) was dissolved in ethanol (2 L) and conc.aq. HCl (60 mL). The solution was stirred at ambient temperature for 48h. and then concentrated under reduced pressure followed byco-evaporations with toluene 3 times to give 66-7 as a pale yellow solid(110 g).

Compound 66-7 (110 g) was dissolved in anhydrous pyridine (1 L). Benzoylchloride (200 mL, 1.67 mol) was added slowly at 0-5° C. The mixture wasstirred at ambient temperature for 45 mins. The reaction was quenchedwith ice and MeOH to form a precipitate. After filtration, the filtratewas washed with MeOH to give 66-8 (200 g, 61.2%) as a white solid.

To a solution of 66-8 (100 g, 269 mmol) in anhydrous THF (1000 ml) wasadded dropwise a solution of lithium tri-tert-butoxyaluminohydride (400ml, 1M, 0.4 mol) at −78° C. under N₂ for 30 mins. The solution wasstirred at −20° C. for 1 h, and TLC (PE: EA=3:1) showed that thereaction was complete. The mixture was quenched with sat.NH₄Cl, anddiluted with EA. After filtration, the filtrate was extracted with EA.The combined layers were dried over Na₂SO₄, and concentrated at lowpressure. The residue was purified by a silica column gel (PE: EA=20:1)to give 66-9 (100 g, 100%) as a colorless oil.

To a stirred solution of PPh₃ (140 g, 382 mol) in CH₂Cl₂ (1000 ml) wasadded 66-9 (100 g, 269 mmol) at −20° C. under N₂. After stirring for 15mins, CBr₄ (177 g, 382 mol) was added dropwise while maintaining thetemperature between −25 and −20° C. under N₂. The mixture was stirredbelow −17° C. for 20 mins. Silica gel was added to the mixture. Themixture was filtered through cold silica column gel and washed with PE:EA (50:1 to 4:1). The combined filtrates were concentrated under reducedpressure at R.T. to give the crude oil product. The residue was purifiedby a silica column gel a second time (PE: EA=50:1 to 4:1) to give 66-10(a-isomer, 64 g, yield: 55%) as a colorless oil.

A mixture of 6-chloro-guanine (55.8 g, 316.5 mol) and t-BuOK (39.5 g,352.7 mmol) in t-BuOH (500 mL) and MeCN (280 mL) was stirred for 30mins. Compound 66-10 (48 g, 105.5 mmol) was added at R.T., and themixture was heated to 50° C. and stirred overnight. The reaction wasmonitored by TLC (PE:EA=2:1). The mixture was quenched with solid NH₄Cl.After stirring for 1 h, the mixture was filtered and washed with MeCN.The filtrate was evaporated at low pressure, and the residue waspurified by a silica gel column to give 66-11 (33 g, 57%).

To a solution of 66-11 (49 g, 93.1 mol) in CH₂Cl₂ (200 mL) was addedAgNO₃ (31.7 g, 186 mmol), collidine (22.5 g, 186 mmol) and MMTrCl (43 g,140 mmol) in small portions under N₂ at 0° C. The mixture was stirred atR.T., and monitored by TLC (PE:EA=4:1). After filtration, the organicphase was washed with NaHCO₃ aqueous and brine. The organic layer wasdried over anhydrous Na₂SO₄ and concentrated at low pressure. Theresidue was purified by a silica gel column (PE:ME=20:1 to 1:1) to give66-12 (70 g, 94.2%).

Sodium (10.1 g, 439 mmol) was dissolved in dry EtOH (600 mL) at 70° C.and then cooled to 0° C. To a solution of 66-12 (70 g, 87.7 mmol) wasadded a freshly prepared NaOEt solution in portions at 0° C., and themixture was stirred for 1 h. at R.T. After TLC and LCMS showed thereaction was completed, the reaction was quenched with carbon dioxide.The mixture was evaporated at low pressure, and the residue was purifiedusing silica gel column chromatography (DCM: MeOH=100:1 to 20:1) to give66-13 (50 g, yield 5%) as a yellow solid.

A mixture of PPh₃ (35 g, 133.5 mol) and I₂ (31.75 g, 125 mmol) inanhydrous pyridine (600 mL) was stirred for 30 mins, and then a solutionof 66-13 (50 g, 83.3 mmol) in pyridine (100 mL) was added at 0° C. Themixture was stirred overnight at R.T. and monitored by TLC(DCM:MeOH=50:1). The reaction was quenched with a sat. NaHCO₃ solution,and extracted with DCM (3×50 mL). The organic phase was dried overanhydrous MgSO₄, and evaporated at low pressure. The residue waspurified using silica gel column chromatography (DCM: MeOH=200:1 to50:1) to give 66-14 (50 g, 84.7%).

To a solution of 66-14 (37 g, 52.1 mmol) in dry THF (400 mL) was addedDBU (16 g, 105 mmol). The mixture was heated to reflux and stirred for 3h. The reaction was monitored by LCMS. The reaction was quenched with asat. NaHCO₃ solution, and extracted with EA. The combined organic layerswere dried over anhydrous Na₂SO₄, and evaporated at low pressure. Theresidue was purified using silica gel column chromatography (PE:EA=10:1to 5:1) to give 66-15 (25 g, 61.1%) as a white solid.

To an ice-cold solution of 66-15 (26 g, 44.6 mmol) in dry MeCN (300 mL)was added NIS (12.68 g, 56 mmol) and NEt₃.3HF (10.6 g, 67 mmol) at 0° C.The reaction was stirred at R.T. for 2 h. and monitored by LCMS. Afterthe reaction was completed, the reaction was quenched with a sat Na₂SO₃and sat. NaHCO₃ solution, and extracted with EA. The organic layer wasseparated, dried over anhydrous Na₂SO₄, and evaporated at low pressure.The residue was purified using silica gel column chromatography (PE:EA=8:1 to 1:1) to give 66-16 (21 g, 64.4%) as a white solid.

To a solution of 66-16 (21 g, 28.8 mol) in CH₂Cl₂ (150 mL) was addedAgNO₃ (9.8 g, 59.6 mmol) and collidine (7 g, 59.8 mmol) and MMTrCl (13.1g, 42.5 mmol) in small portions under N₂ at 0° C. The mixture wasstirred at R.T., and the reaction was monitored by TLC (PE:EA=2:1).After filtration, the solution was washed with sat. aq. NaHCO₃ andbrine. The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated at low pressure. The residue was purified by a silica gelcolumn to give 66-17 (25 g, yield 86.5%).

To a solution of 66-17 (22 g, 22 mmol) in dry DMF (500 mL) was addedNaOBz (31.9 g, 220 mmol) and 15-crown-5 (48.4 g, 220 mmol), and themixture was stirred for 72 h. at 95° C. The mixture was diluted with EA,washed with water and brine, and dried over MgSO₄. The organic layer wasevaporated at low pressure, and the residue was purified using a silicagel column chromatography to give 66-18 (15 g, 68.8%) as a white solid.

Compound 66-18 (15.2 g, 15.3 mmol) was co-evaporated with anhydroustoluene 3 times to remove H₂O. The compound was treated with NH₃ in MeOH(7 N, 200 mL) at R.T. The mixture was stirred for 18 h at R.T., and thereaction was monitored by LCMS. The residue was concentrated at lowpressure, and purified using silica gel column chromatography to give66-19 (11 g, 81%) as a white solid.

To a stirred solution of 66-20 (14 g, 15.73 mmol) in anhydrous CH₃CN(150 mL) was added N-methylimidazole (23.5 g, 283.9 mmol) at 0 to 5° C.(ice/water bath) followed by a solution ofphenyl(cyclohexanoxy-L-alaninyl)phosphorochloridate (16.33 g, 47.2 mmol,dissolved in 50 mL of CH₃CN). The solution was stirred at 0 to 5° C. for12 h and then diluted with EA. The solution was washed 50% aqueouscitric acid solution and brine. The organic layer was separated, driedover anhydrous MgSO₄ and filtered. The filtrate was concentrated at lowpressure, and the residue was purified on silica gel with PE: EA=5:1 asthe eluent to give 66-20 (17.62 g, 93.4%) as a white solid.

Compound 66-20 (17.62 g, 14.7 mmol) was dissolved in 80% AcOH (200 mL),and the mixture was stirred overnight at R.T. After removal of thesolvents, the reside was purified on silica gel using PE:EA=2:1 toeluent to give the crude product, which was purified on viareverse-phase HPLC using acetonitrile and water to give compound 66(5.25 g, yield 66%) as a white solid. ESI-LCMS: m/z 655 [M+H]⁺.

Example 49

To a solution of the nucleoside (300 mg, 1.09 mmol) and proton-sponge(467 mg, 2.18 mmol) in anhydrous CH₃CN (5 mL) at 0° C. under N₂ wasadded dropwise a solution of phosphorus oxychloride (330 mg, 2.18 mmol)in anhydrous CH₃CN (1 mL). The mixture was stirred at 0° C. for 30 mins,and the hydrogen chloride salt of (S)-ethyl 2-aminopropanoate (998 mg,6.52 mmol) and triethylamine (1.5 mL, 10.87 mmol) at 0° C. were added.The mixture was stirred overnight at 30° C. The reaction was quenchedwith water, and extracted with EA (3×20 mL). The organic layer wasconcentrated at low pressure, and the residue was purified by reversephase HPLC to give compound 67 (20 mg, 3%) as a white solid. ESI-LCMS:m/z 535 [M−F]⁺.

Example 50

To a solution of sodium hydrosulfide (4.26 g, 76.0 mmol) in EtOH (100mL) was added t-butyryl chloride (76.2 mmol; 9.35 mL) dropwise at 0° C.,and the mixture was stirred at R.T. for 1 h. A solution of2-(2-chloroethoxy)ethanol (57 mmol; 6.0 mL) and TEA (21 mL, 120 mmol)was added, and the mixture was heated at reflux for 60 h. The mixturewas filtered, and then concentrated to a small volume. The residue wasdissolved in EA, and then washed with water, sat. aq. NaHCO₃ and brine.The organic phase was dried over Na₂SO₄, filtered and concentrated invacuo. The crude product (10.0 g) was isolated and 5 grams were purifiedby silica gel flash column chromatography using a gradient of 0 to 100%EA in hexane to give 59-3 (4.5 g, 22 mmol) as a clear, colorless oil.¹H-NMR (CDCl₃): 3.70-3.74 (m, 2H), 3.5-3.65 (m, 4H), 3.1 (t, 2H), 1.25(s, 9H).

A solution 59-3 (4.5 g; 21.8 mmol) and triethylamine (6.7 mL, 87.2 mmol)in tetrahydrofuran (50 mL) was added dropwise over 1 h to a stirredsolution of N,N-diisopropylphosphorodichloridite (2.0 mL, 10.9 mmol) inTHF (50 mL) under argon at −78° C. The mixture was stirred at R.T. for 2h, and then diluted with EA (200 mL). The mixture was washed with sat.aq. NaCl and dried over Na₂SO₄. After filtration, the filtrate wasevaporated under reduced pressure to give a pale yellow oil.Purification by flash column chromatography using a gradient of EA(0-5%) in hexane containing 5% triethylamine afforded 59-4 (2.5 g, 4.25mmol) as a clear, colorless oil. ¹H-NMR (CDCl₃): 3.70-3.82 (m, 4H),3.57-3.65 (m, 10H), 3.1 (t, 4H), 1.25 (s, 18H), 1.17 (t, 12H); ³¹P-NMR(CDCl₃): 148.0 ppm.

Compound 59-5 (285 mg, 0.9 mmol) and DCI (175 mg, 1.5 mmol) werecoevaporated twice with ACN and then dissolved in ACN (5 mL). Compound59-4 (790 mg, 1.35 mmol) in ACN (4 mL) was added, and the reaction wasmonitored by TLC. After 15 mins, tert-butylhydroperoxide (0.5 mL of 5.5Msolution in decane) was added, and the mixture was stirred for 10 mins.The mixture was diluted with EA (25 mL), washed with sat. aq. NaHCO₃ andsat. aq. NaCl solution, dried over Na₂SO₄, filtered and concentrated.Purification by flash column chromatography using a gradient of EA(0-100%) in hexane afforded 59-6 (0.17 g, 0.22 mmol) as a white solid.Compound 59-6 was dissolved in 80% aq. HCOOH (5 mL). After 30 mins atR.T., the solvent was removed and coevaporated twice with toluene. Theresidue was dissolved in methanol (10 mL) and TEA (0.2 mL) was added.After 2 mins at R.T., the solvent was removed in vacuo. Purification byflash column chromatography using a gradient of methanol (0-15%) in DCMafforded compound 59 (90 mg). ¹H-NMR (CDCl₃): 7.40 (d, 1H), 6.1 (s, 1H),5.83 (d, 1H), 4.3 (t, 2H), 4.1-4.2 (m, 6H), 3.70-3.82 (m, 4H), 3.57-3.65(m, 4H), 3.1 (t, 4H) 1.61 (s, 8H), 1.3 (s, 3H), 1.23 (s, 18H). ³¹P-NMR(CDCl₃): −1.55 ppm.

Example 51

Compound 60-1 (6.0 g, 31.6 mmol) was prepared using a similar procedureto the one used to prepared 59-3 using 4-chlorobutanol. Compound 60-1was obtained as a clear, colorless oil. ¹H-NMR (CDCl₃): 3.67 (s, 2H),2.86 (m, 2H), 1.65 (m, 4H), 1.25 (s, 9H).

Compound 60-2 (2.14 g, 4.0 mmol) was prepared using a similar procedureto the one used to prepared 59-4. Compound 60-2 was obtained as a clear,colorless oil. ¹H-NMR (CDCl₃): 3.67 (m, 6H), 2.86 (t, 4H), 1.65 (m, 8H),1.25 (s, 18H), 1.17 (t, 12H). ³¹P-NMR (CDCl₃): 143.7 ppm.

Compound 60-3 (0.23 g, 0.22 mmol) was prepared using a similar procedureto the one used to prepared 59-6 using 59-5 and 60-2. Compound 60-3 wasobtained as a white solid. Using a similar procedure to the one used toprepared compound 59, 60-3 was used to prepare compound 60 (170 mg).¹H-NMR (CDCl₃): 7.40 (d, 1H), 6.1 (s, 1H), 5.83 (d, 1H), 4.3 (t, 2H),4.1-4.2 (m, 6H), 2.8 (t, 4H), 1.78 (m, 4H), 1.69 (s, 8H), 1.3 (s, 3H),1.23 (s, 18H). ³¹P-NMR (CDCl₃): −1.56 ppm.

Example 52

Compound 58-1 was prepared according to the procedure described inLefebre et al. J. Med. Chem. (1995) 38:3941-3950, which is herebyincorporated by reference for the limited purpose of its description ofthe preparation of 58-1.

Compound 58-2 (0.33 g, 0.5 mmol) was prepared using a similar procedureto the one used to prepared 59-6 using 59-5 and 58-1. Compound 58-2 wasobtained as a white solid. Using a similar procedure to the one used toprepared compound 59, 58-2 was used to prepare compound 58 (130 mg).¹H-NMR (CDCl₃): 7.40 (d, 1H), 6.1 (s, 1H), 5.83 (d, 1H), 4.3 (t, 2H),4.1-4.2 (m, 6H), 3.2 (t, 4H), 1.69 (s, 4H), 1.3 (s, 3H), 1.23 (s, 18H);³¹P-NMR (CDCl₃): −2.4 ppm.

Example 53

Compound 47-1 (1.0 g, 3.53 mmol) was coevaporated with anhydrouspyridine 3 times to remove H₂O. To an ice-cold solution of 47-1 inanhydrous pyridine (9 mL) was added TsCl (808 mg, 4.24 mmol) in pyridine(3 mL) drop-wise at 0° C., and the mixture was stirred for 18 h. at 0°C. The reaction was monitored by LCMS, and then quenched with H₂O. Afterconcentration at low pressure, the residue was dissolved in EA (50 mL).The solution was washed with sat. NaHCO₃ solution and brine. The organiclayer was dried over anhydrous Na₂SO₄ and filtered. The filtrate wasevaporated at low pressure, and the residue was purified by silica gelcolumn chromatography (1% MeOH in DCM) to give 47-2 (980 mg, 63%) as awhite solid.

To a solution of 47-2 (980 mg, 2.24 mmol) in acetone (10 mL) was addedNaI (1.01 g, 6.73 mmol), and the mixture was heated to reflux overnight.The reaction was monitored by LCMS. After the reaction was completed,the mixture was concentrated at low pressure. The residue was dissolvedin EA (50 mL). The solution was washed with brine, and dried overanhydrous Na₂SO₄. The solution was evaporated at low pressure, and theresidue was purified by silica gel column chromatography (1% MeOH inDCM) to give 47-3 (700 mg, 79%) as a solid.

To a solution of 47-3 (700 mg, 1.78 mmol) in dry THF (9 mL) was addedDBU (817 mg, 5.34 mmol), and the mixture was heated to 60° C. Themixture was stirred overnight, and monitored by LCMS. The reaction wasquenched with sat. NaHCO₃ and extracted with EA (3×50 mL). The organicphase was dried over anhydrous Na₂SO₄, and filtered. The filtrate wasevaporated at low pressure, and the residue was purified by silica gelcolumn chromatography (1% MeOH in DCM) to give 47-4 (250 mg, 53%) as awhite solid.

To an ice-clod solution of 47-4 (250 mg, 0.94 mmol) in dry MeCN (5 mL)was added NEt₃0.3HF (151 mg, 0.94 mmol) and NIS (255 mg, 1.13 mmol). Themixture was stirred at R.T., for 3 h., and checked by LCMS. The reactionwas quenched with sat Na₂S₂O₃ and sat. NaHCO₃ solution, and extractedwith EA (3×50 mL). The organic layer was separated, dried over anhydrousNa₂SO₄, and evaporated at low pressure. The residue was purified bysilica gel column chromatography (2% acetone in DCM) to give 47-5 (170mg, 44%).

To a solution of 47-5 (270 mg, 0.65 mmol) in dry DCM (4 mL) was addedDMAP (158.6 mg, 1.3 mmol), and BzCl (137 mg, 0.98 mmol). The mixture wasstirred for 4-5 h. at R.T., and checked by LCMS. The mixture was dilutedwith CH₂Cl₂, and washed with sat. NaHCO₃ solution and brine. The organiclayer was evaporated at low pressure, and the residue was purified bysilica gel column chromatography (20% EA in PE) to give 47-6 (290 mg,86%) as a solid.

To a solution of 47-6 (900 mg, 1.74 mmol) in dry DMF (45 mL) was addedNaOBz (2.5 g, 17.4 mmol) and 15-crown-5 (4.5 g, 20.9 mmol). The mixturewas stirred for 48 h at 90-100° C. The mixture was diluted with EA (100mL), and washed with brine. The organic layer was evaporated at lowpressure, and the residue was purified by silica gel columnchromatography (20% EA in PE) to give 47-7 (500 mg, 56%) as a solid.

To a solution of 47-7 (500 mg, 0.98 mmol) in anhydrous CH₃CN (5 mL) wasadded TPSCl (741 mg, 2.45 mmol), DMAP (299.6 mg, 2.45 mmol) and NEt₃(248 mg, 2.45 mmol) at R.T., and the mixture was stirred overnight. Themixture was then treated with NH₃ in THF (5 mL) and then stirred foranother 30 mins. The mixture was diluted with EA (100 mL). The solutionwas washed with 0.5% AcOH solution. The organic solvent was dried overanhydrous MgSO4, and concentrated at low pressure. The crude product waspurified by silica gel column chromatography (2% Acetone in DCM) to give47-8 (257 mg, 51.6%) as a white solid. ESI-MS: m/z 509 [M+H]⁺.

Compound 47-8 (80 mg, 0.16 mmol) was dissolved in n-butylamine (3 mL).The mixture was kept overnight at R.T. and evaporated. The residue wascrystallized from methanol to give compound 47 (30 mg). The motherliquor was purified by RP HPLC on Synergy 4 micron Hydro-RP column(Phenominex). A linear gradient of methanol from 0 to 30% in 50 mMtriethylammonium acetate buffer (pH 7.5) was used for elution. Thecorresponding fractions were combined, concentrated and lyophilized 3times to remove excess of buffer to yield additional compound 47 (13mg). Compound 47 (total yield 43 mg, 73%). MS: m/z 299.7 [M−1]⁻.

Example 54

To a stirred solution of POCl₃ (2.0 g, 13 mmol) in anhydrous DCM (10 mL)was added 1-naphthol (1.88 g, 13 mmol) at −70° C., and TEA (1.31 g, 13mmol) in DCM (3 mL) dropwise at −70° C. The mixture was gradually warmedto R.T. and stirred for 1 h. Crude 83-1 was obtained.

To a stirred solution of (S)-isopropyl 2-aminopropanoate hydrochloride(2.17 g, 13 mmol) in DCM (10 mL) was added crude 83-1 at −70° C. TEA(2.63 g, 26 mmol) was added to the stirred solution dropwise at −70° C.The mixture was gradually warmed to R.T. and stirred for 2 h. Thereaction was monitored by LCMS and quenched with n-propylamine. Themixture was concentrated at low pressure, and the residue was purifiedby a silica gel column (PE:MTBE=5:1˜1:1) to give pure 83-2 (1.6 g, 35%).

To a solution of 83-(A) (300 mg, 0.337 mmol) and NMI (276 mg, 3.37 mmol)in anhydrous CH₃CN (4 mL) was added 83-2 (240 mg, 0.674 mol, in DCM (5mL)) at 0° C. The mixture was stirred at R.T. for 10 h. The reaction wasmonitored by LCMS. The reaction was quenched with water, and extractedwith CH₂Cl₂ (3×20 mL). The organic phase was dried over anhydrous MgSO4,and concentrated at low pressure. The residue was purified by sil-gel(PE:EA=5:1˜2:1) to give 83-3 (380 mg, 93%).

Compound 83-3 (380 mg, 0.314 mmol) was dissolved in CH₃COOH (80%, 8 mL),and stirred at 40-50° C. for 2.5 h. The reaction was monitored by LCMS.The mixture was concentrated at low pressure, and the residue waspurified by chromatography (PE:EA=1:1˜EA) to give crude compound 83. Thecrude product was purified by prep-HPLC (neutral system, NH₄HCO₃) togive pure compound 83 (70 mg, 80%) as a white solid. ESI-MS: m/z 665.1[M+H]⁺.

Example 55

A solution of 79-1 (16.70 g, 0.363 mol) and TEA (36.66 g, 0.363 mol) inCH₂Cl₂ (150 mL) was added dropwise to a stirred solution of POCl₃ (55.65g, 0.363 mol) in DCM (100 mL) over 25 mins at −78° C. After the mixturewas stirred for 2 h. at R.T., the triethylamine hydrochloride salt wasfiltered, and washed with CH₂Cl₂ (˜100 mL). The filtrate wasconcentrated at low pressure, and the residue was distilled under highvacuum (˜10 mm Hg) with a cow-head fraction collector. The product wascollected between 45° C. (distillation head temperature) as a colorlessliquid (30.5 g, 50% yield). ¹H-NMR (400 MHz, CDCl₃) δ=4.44 (dq, J=10.85,7.17 Hz, 2H), 1.44-1.57 (m, 3H); ³¹P-NMR (162 MHz, CDCl₃) δ=6.75 (br.s., 1P).

To a stirred suspension of 83-A (93 mg, 0.15 mmol) in CH₂Cl₂ (1 mL) wasadded TEA (61 mg, 0.15 mmol) at R.T. The mixture was cooled to −20° C.,and then was treated with a 79-2 (35 mg, 0.21 mmol) solution dropwiseover a period of 10 mins. The mixture was stirred at this temperaturefor 15 min., and then was treated with NMI (27 mg, 0.33 mmol). Themixture was stirred at −20° C., and then slowly warmed to R.T. Themixture was stirred overnight. The mixture was suspended in EA (15 mL),washed with brine (10 mL) and dried over anhydrous sodium sulfate. Thesolution was concentrated at low pressure, and the residue was purifiedby chromatography (DCM: MeOH=100:1) to give 79-3 (60 mg, yield: 56%) asa solid.

A solution of 79-3 (60 mg, 0.085 mmol) in 80% AcOH aqueous (2 mL) wasstirred at R.T. for 2 h. The mixture was concentrated under reducedpressure, and the residue was purified by a silica gel column elutingDCM/MeOH=50/1 and prep-HPLC to give compound 79 (23 mg, 62%) as a whitesolid. ESI-MS: m/z 436.3 [M+H]⁺.

Example 56

Compound 80-2 was prepared using a similar procedure as for thepreparation of 79-2 using a solution of iso-butanol (23.9 g, 322.98mmol) and POCl₃ (49.5 g, 322.98 mmol). Compound 80-2 (26 g, 42% yield)was obtained as a colorless liquid. ¹H-NMR (400 MHz, CDCl₃) δ=4.10 (dd,J=9.04, 6.39 Hz, 2H), 2.09 (dq, J=13.24, 6.67, 6.67, 6.67, 6.67 Hz, 1H),1.01 (d, J=6.62 Hz, 6H); ³¹P-NMR (162 MHz, CDCl₃) δ=7.06 (br. s., 1P).

To a stirred suspension of 83-A (310 mg, 0.5 mmol) in CH₂Cl₂ (3 mL) wasadded TEA (202 mg, 2 mmol) at R.T. The mixture was cooled to −20° C.,and then was treated with 80-2 (134 mg, 0.7 mmol). The mixture wasstirred at this temperature for 15 mins and then was treated with NMI(90 mg, 1.1 mmol). The mixture was stirred at −20° C. for 1 h., and thenslowly warmed to R.T. overnight. The mixture was suspended in EA (15mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate.The organic phase was concentrated at low pressure, and the residue waspurified by silica column gel (DCM: MeOH=100:1) to give 80-3 (310 mg,yield: 84%) as a solid.

A solution of 80-3 (310 mg, 0.43 mmol) in 80% AcOH aqueous (4 mL) wasstirred at R.T. for 2 h. The mixture was concentrated at low pressure,and the residue was purified by a silica gel column elutingDCM/MeOH=50/1 and prep-HPLC to give compound 80 (79 mg, 50%) as a whitesolid. ESI-MS: m/z 464.0 [M+H]⁺.

Example 57

Compound 81-2 was prepared using a similar procedure as for thepreparation of 79-2 using a solution of isopropyl alcohol (21 g, 350mmol) and POCl₃ (53.6 g, 350 mmol). Compound 81-2 (40.5 g, 65% yield)was obtained as a colorless liquid. ¹H-NMR (400 MHz, CDCl₃) δ=4.94-5.10(m, 1H), 1.48 (d, J=6.17 Hz, 6H); ³¹P-NMR (162 MHz, CDCl₃) δ=5.58 (br.s., 1P).

Compound 81-3 was prepared using a similar procedure as for thepreparation of 80-3 using 81-2 (124 mg, 0.7 mmol) and 83-A (310 mg, 0.5mmol). Compound 81-3 (300 mg, 83%) was obtained as a solid.

Compound 81 was prepared using a similar procedure as for thepreparation of compound 80 using 81-3 (300 mg, 0.41 mmol) in 80% AcOHaqueous (4 mL). Compound 81 (80 mg, 43%) was obtained as a white solid.ESI-MS: m/z 450.0 [M+H]⁺.

Example 58

To an ice cooled solution of 82-1 (50 g, 204.9 mmol) in dry Py (400 mL)was added TIPDSCl (70.78 g, 225.4 mmol) dropwise. The mixture wasstirred at R.T. for 16 h, and then concentrated at low pressure. Theresidue was purified by chromatography using 20% EA in PE to generate82-2 (111.5 g, 100%) as a white solid.

To a solution of 82-2 (50 g, 103 mmol) in anhydrous CH₃CN (400 mL) wasadded IBX (43 g, 153 mmol) at R.T. The mixture was refluxed overnightand monitored by TLC (PE:EA=1:1). The precipitate was filtered off, andthe filtrate was concentrated to give the crude 82-3 (50 g, 99%) as awhite solid.

To a solution of trimethylsilylacetylene (20 g, 200 mmol) in anhydrousTHF (400 mL) was added dropwise n-BuLi (80 mL, 200 mL) at −78° C. Themixture was stirred at −78° C. for 30 mins, and then warmed to R.T for10 mins. Compound 82-3 (30 g, 60 mmol) in THF (100 mL) was added to themixture dropwise at −78° C. The mixture was stirred at −78° C. for 1 hand then slowly warmed to R.T. The mixture was stirred for 20 mins, andthen the reaction was quenched with a sat. NH₄Cl solution at −78° C. Themixture was diluted with EA. The organic phase was washed with brine,dried over anhydrous Na₂SO₄, and concentrated at low pressure. Theresidue was purified by silica gel column chromatography (15% EA in PE)to give 82-4 as a white solid (14 g, 50%).

Compound 82-4 (14 g, 24 mmol) was dissolved in anhydrous toluene (100mL) under N₂ and cooled to −78° C. DAST (19 g, 120 mmol) was addeddropwise at −78° C. and stirring was continued for 1.5 h. The mixturewas diluted with EA and poured into a sat. NaHCO₃ solution. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated at low pressure. The residue was purified by silica gelchromatography (20% EA in PE) to give 82-5 as a white solid (12 g, 81%).

A mixture of 82-5 (12 g, 20 mmol) and NH₄F (11 g, 30 mmol) in MeOH (150mL) was refluxed for 2 h. After cooling to R.T, the mixture wasconcentrated at low pressure, and the residue was purified by silica gelcolumn chromatography (5% MeOH in DCM) to give 82-6 (3.1 g, 58%) as awhite solid.

To a solution of 82-6 (3.1 g, 11.6 mmol) in dry Py (50 mL) was addedimidazole (3.1 g, 46.4 mmol) and TBSCl (5.2 g, 34.8 mmol). The mixturewas stirred at 50-60° C. for 3 h. The mixture was concentrated at lowpressure, and the residue was dissolved in EA (100 mL). The solution waswashed with brine, dried over anhydrous Na₂SO₄, and concentrated at lowpressure. The residue was purified by silica gel chromatography (20% EAin PE) to give 82-7 as a white solid (5 g, 86%).

To a solution of 82-7 (4.5 g, 9 mmol) in 1,4-dioxane (45 mL) was addedCuBr (643 mg, 4.5 mmol), dicyclohexylamine (3.3 g, 18 mmol) andparaformaldehyde (675 mg, 22.5 mmol). The mixture was refluxed for 24 hand then cooled to R.T. The reaction was quenched with a sat. NH₄Clsolution. The mixture was extracted with EA (3×100 mL). The organiclayer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated at low pressure. The residue was purified by silica gelcolumn chromatography (15% EA in PE) to give 82-8 as a white solid (2.0g, 43%).

A mixture of 82-8 (2 g, 4 mmol) and NH₄F (2.2 g, 60 mmol) in MeOH (20mL) was refluxed overnight. After cooling to R.T., the mixture wasconcentrated at low pressure, and the residue was purified by silica gelcolumn chromatography (5% MeOH in DCM) to give 82-9 (946 mg, 83%) as awhite solid.

To a stirred suspension of 82-9 (946 mg, 3.33 mmol), PPh₃ (1.3 g, 5mmol), imidazole (453 mg, 6.66 mmol) and pyridine (3 mL) in anhydrousTHF (12 mL) was added a solution of I₂ (1 g, 4.33 mmol) in THF (4 mL)dropwise at 0° C. The mixture was warmed to R.T. and stirred for 16 h.The reaction was quenched with a sat. Na₂S₂O₃ aq. solution and extractedwith EA (3×60 mL). The organic layer was dried over Na₂SO₄ andconcentrated at low pressure. The residue was purified on a silica gelcolumn (2% MeOH in DCM to 5% MeOH in DCM) to afford 82-10 (2.1 g, crude)as a white solid.

To a solution of 82-10 (2.1 g, 5.3 mmol) in THF (15 mL) was added DBU(15 g, 100 mmol) and the mixture stirred for 30 mins. The mixture wasdiluted with EA and neutralized with acetic acid. The solution waswashed with brine, dried over anhydrous Na₂SO₄, and concentrated at lowpressure. The residue was purified by silica gel column chromatography(1.5% MeOH in DCM) to give 82-11 as a white solid (800 mg, 90%).

To an ice-cooled solution of 82-11 (800 mg, 3 mmol) in dry MeCN (1.5 mL)was added NEt₃.3HF (484 mg, 3 mmol) and NIS (1.68 g, 7.5 mmol). Themixture was stirred at R.T. for 30 mins., and the reaction was monitoredby LCMS. The reaction was quenched with sat. Na₂S₂O₃ and sat. NaHCO₃solution, and extracted with EA (3×50 mL). The organic layer was driedover anhydrous Na₂SO₄, and concentrated at low pressure. The residue waspurified by a silica gel column (25% EA in PE) to afford 82-12 (850 mg,68%) as a white solid.

To a solution of 82-12 (850 mg, 2 mmol) in dry DCM (10 mL) was addedDMAP (488 mg, 4 mmol) and BzCl (422 mg, 3 mol). The mixture was stirredfor 4-5 h at R.T., and the reaction was monitored by LCMS. The mixturewas diluted with CH₂Cl₂ (40 mL), and washed with a sat. NaHCO₃ solution.The organic layer was dried over anhydrous Na₂SO₄, and filtered. Thefiltrate was evaporated at low pressure, and the residue was purified bysilica gel column chromatography (20% EA in PE) to give 82-13 (900 mg,87%) as a white foam.

Tetra-butylammonium hydroxide (21 mL as 54-56% aqueous solution, ˜42mmol, 24 eq.) was adjusted with TFA to pH˜4 (˜3.5 mL), and the solutionwas treated with a solution of 82-13 (900 mg, 1.7 mmol) in DCM (21 mL).m-Cloroperbenzoic acid (2.1 g, 60-70%, ˜8.75 mmol, ˜5 eq.) was addedportionwise under vigorous stirring, and the mixture was stirredovernight. The mixture was diluted with CH₂Cl₂ (30 mL), and washed witha saturated NaHCO₃ solution. The organic layer was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography in (40-70%EA in PE) to give 82-14 as an oil. The residue was purified by TLC (50%EA in PE) to give pure 82-14 (350 mg 50%).

Compound 82-14 (350 mg, 0.86 mg) was treated with 7N NH₃ in MeOH (15mL). The mixture was stirred for 2-3 h and monitored by TLC. The mixturewas concentrated at low pressure, and the residue was purified by silicagel column chromatography (5% isopropanol in DCM) to give 82-15 (250 mg,96%) as a white solid. ¹H NMR (CD₃OD, 400 M Hz) δ=7.75 (d, J=7.9 Hz,1H), 6.60-6.35 (m, 1H), 5.72 (d, J=8.2 Hz, 1H), 5.37-5.25 (m, 1H),5.17-5.06 (m, 1H), 5.04-4.94 (m, 1H), 4.59-4.29 (m, 1H), 3.87-3.70 (m,2H).

To a stirred solution of 82-16 (3.79 g, 18 mmol) and 82-17 (3 g, 18mmol) in anhydrous DCM (60 mL) was added with a solution of TEA (4 g, 39mmol) in DCM (40 mL) dropwise at −78° C., and the mixture was stirredfor 2 h. The mixture was concentrated at low pressure, and the residuewas dissolved in methyl-butyl ether. The precipitate was removed byfiltration, and the filtrate was concentrated to give the crude product.The residue was purified by dry column chromatography (anhydrous DCM) togive pure 82-18 as a colorless oil (3 g, 54%).

Compound 82-15 (200 mg, 0.66 mmol) was coevaporated with toluene 3 timesto remove H₂O. Compound 82-15 was treated with MeCN (1.5 mL) and NMI(541 mg, 6.6 mmol). The mixture was stirred at R.T., and then 82-18 (403mg, 1.32 mmol) in MeCN (0.5 mL) was added. The residue was purified by asilica gel column (5% iPrOH in DCM) to give the crude product, which waspurified by HPLC (0.1% HCOOH in water and MeCN) to give compound 82 (33mg, 9%). ESI-LCMS: m/z 594 [M+Na]⁺.

Example 59

To a stirred solution of POCl₃ (2.0 g, 13 mmol) in anhydrous DCM (10 mL)was added 1-naphthol (1.88 g, 13 mmol) at −70° C. and TEA (1.31 g, 13mmol) in DCM (3 mL) dropwise at −70° C. The mixture was gradually warmedto R.T., and stirred for 1 h. A crude solution of 84-1 was obtained.

To a stirred solution of (S)-isobutyl 2-aminopropanoate hydrochloride(2.35 g, 13 mmol) in DCM (20 mL) was added TEA (2.63 g, 26 mmol) and acrude solution of 84-1 at −70° C. The mixture was gradually warmed toR.T., and stirred for 2 h. The reaction was monitored by LCMS andquenched with n-propylamine. The solvent was evaporated at low pressure,and the residue was purified by chromatography (PE:MTBE=5:1˜1:1) to givepure 84-2 (1.8 g, 37%).

To a solution of 83-A (300 mg, 0.337 mmol) and NMI (276 mg, 3.37 mmol)in anhydrous CH₃CN (4 mL) was added 84-2 (249 mg, 0.674 mol, in DCM (5mL)) at 0° C. The mixture was stirred at R.T. for 10 h. The reaction wasmonitored by LCMS, and then quenched with H₂O. The mixture was extractedwith CH₂Cl₂ (3×20 mL). The organic phase was dried over anhydrous MgSO4,and concentrated at low pressure. The residue was purified bychromatography using PE:EA=5:1-2:1 as the eluent to give 84-3 (360 mg,87%).

Compound 84-3 (360 mg, 0.294 mmol) was dissolved in CH₃COOH (80%, 8 mL),and stirred at 40-50° C. for 2.5 h. The reaction was monitored by LCMSand then quenched with MeO. The mixture was concentrated at lowpressure, and the residue was purified by chromatography using PE:EA=1:1as the eluent to generate crude compound 84. The product purified byprep-HPLC (neutral system, NH₄HCO₃) to give compound 84 (70 mg, 75%) asa white solid. ESI-MS: m/z 679.2 [M+H]⁺.

Example 60

To a stirred solution of POCl₃ (2.0 g, 13 mmol) in anhydrous DCM (10 mL)was added phenol (1.22 g, 13 mmol) at −70° C. and TEA (1.31 g, 13 mmol)in DCM (3 mL) dropwise at −70° C. The mixture was gradually warmed toR.T., and stirred for 1 h. A crude solution of 85-1 was obtained.

Compound 85 was prepared using a similar procedure as for thepreparation of compound 84 using 85-2 (205 mg, 0.674 mol, in DCM (5 mL)obtained from (S)-isopropyl 2-aminopropanoate hydrochloride and 85-1)and 83-A (300 mg, 0.337 mmol). Compound 85 (50 mg, 74%) was obtained asa white solid. ESI-MS: m/z 615.2 [M+H]⁺.

Example 61

Compound 86 was prepared using a similar procedure as for thepreparation of compound 84 using 86-2 (214 mg, 0.674 mol, in DCM (5 mL)obtained from (S)-isobutyl 2-aminopropanoate hydrochloride and 86-1) and83-A (300 mg, 0.337 mmol). Compound 86 (70 mg, 87%) was obtained as awhite solid. ESI-MS: m/z 629.2 [M+H]⁺.

Example 62

Compound 87 was prepared using a similar procedure as for thepreparation of compound 84 using 87-2 (223 mg, 0.674 mol, DCM (5 mL)obtained from (S)-cyclopentyl 2-aminopropanoate hydrochloride and 87-1)and 83-A (300 mg, 0.337 mmol). Compound 87 (62 mg, 71%) was obtained asa white solid. ESI-MS: m/z 641.2 [M+H]⁺.

Example 63

Compound 88 was prepared using a similar procedure as for thepreparation of compound 84 using 88-2 (223 mg, 0.674 mol, DCM (5 mL),obtained from (S)-3-pentyl 2-aminopropanoate hydrochloride and 88-1) and83-A (300 mg, 0.337 mmol). Compound 88 (42 mg, 60%) was obtained as awhite solid. ESI-MS: m/z 643.2 [M+H]⁺.

Example 64

A stirred solution of phosphoryl trichloride (1.00 g, 6.58 mmol) and5-quinoline (955 mg, 6.58 mmol) in anhydrous DCM (50 mL) was treatedwith a solution of TEA (665 mg, 6.58 mmol) in DCM (10 mL) at −78° C. Themixture was gradually warmed to R.T., and stirred for 2 h. The solutionwas cooled to −78° C. and then treated with (S)-neopentyl2-aminopropanoate hydrochloride (1.28 g, 6.58 mmol). TEA (1.33 g, 13.16mmol) was added dropwise at −78° C. The mixture was gradually warmed toR.T., and stirred for 2 h. The mixture was concentrated at low pressure,and the residue was dissolved in methyl-butyl ether. The precipitate wasfiltered off, and the filtrate was concentrated at low pressure. Theresidue was purified by a silica gel column (pure AcOEt) to give 89-1 ascolorless oil (500 mg, 20%).

To a solution of 89-2 (300 mg, 0.337 mmol) and NMI (276.6 mg, 3.37 mmol)in anhydrous CH₃CN (0.9 mL) was added 89-1 (388 mg, 1.011 mmol) in CH₃CN(0.3 mL) dropwise at 0° C. The mixture was stirred at R.T. overnight.The reaction was quenched with water, and extracted with AcOEt. Theorganic phase was washed with brine, dried over anhydrous sodiumsulfate, and concentrated at low pressure. The residue was purified bysilica gel column (33% EA in PE) to give 89-3 as a yellow powder (300mg, 71.9%).

Compound 89-3 (300 mg, 0.243 mmol) was dissolved in 80% CH₃COOH (3 mL),and the mixture was stirred at 60° C. for 2.5 h. The mixture waspartitioned between AcOEt and water. The organic layer phase was washedby brine, dried over sodium sulfate and concentrated at low pressure.The residue was purified by silica gel column (50% EA in PE) to givecompound 89 as a yellow powder (81 mg, crude product). The crude product(81 mg) was purified by RP HPLC to give compound 89 as a white solid.(28.7 mg, 17.1%). ESI-LCMS: m/z 694.1 [M+H]⁺.

Example 65

Compound 90-1 was prepared using a similar procedure as for thepreparation of compound 89-1 using phosphoryl trichloride (2.00 g, 13.16mmol), 1-naphthol (1.882 g, 13.16 mmol) and (S)-neopentyl2-aminopropanoate hydrochloride (2.549 g, 13.16 mmol). Compound 90-1(600 mg, 12%) was obtained as a colorless oil.

A solution of 90-2 (230 mg 0.26 mmol) and NMI (212 mg 2.60 mmol) inanhydrous CH₃CN (1 mL) was treated with a solution of 90-1 (300 mg 0.78mmol) in anhydrous CH₃CN (0.5 mL) at R.T. The mixture was stirred atR.T. overnight. The reaction was quenched with water, and extracted withEA (3×20 mL). The organic layer was washed with brine, dried byanhydrous sodium sulfate, and concentrated at low pressure. The residuewas purified by a silica gel column (CH₃OH in CH₂Cl₂ from 1% to 5%) togive 90-3 (300 mg, 93%) as a white solid.

Compound 90-3 (300 mg, 0.24 mmol) was dissolved in CH₃COOH (80%, 5 mL).The mixture was stirred at 60° C. for 2.5 h. The mixture was dilutedwith EA (30 mL) and washed with brine. The organic phase was dried overanhydrous sodium sulfate, and concentrated at low pressure. The residuewas purified by a silica gel column (CH₃OH in CH₂Cl₂ from 1% to 5%) togive crude compound 90 (105 mg). The crude product was purified by HPLC(0.1% NH₄HCO₃ in water and CH₃CN) to give compound 90 (45 mg, 26%) as awhite solid. ESI-LCMS: m/z 693.2 [M+H]⁺.

Example 66

A stirred solution of 91-1 (2.00 g, 13.99 mmol) and 91-2 (2.00 g, 13.99mmol) in anhydrous DCM (8 mL) was treated with a solution of TEA (3.11g, 30.8 mmol) in DCM (20 mL) dropwise at −78° C. The mixture was stirredfor 2 h. at −78° C. and then gradually warmed to R.T. The organicsolvent was removed at low pressure, and the residue was dissolved inmethyl-butyl ether. The precipitate was filtered off, and the filtratewas concentrated at low pressure. The residue was purified on a silicagel column (dry DCM) to give 91-3 as colorless oil (1 g, 20.96%).

Compound 91-4 (260 mg, 0.29 mmol) was coevaporated with toluene 3 timesto remove H₂O. Dried 91-4 was treated with MeCN (0.8 mL) and NMI (240mg, 2.9 mmol) and then stirred for 10 mins. The mixture was treated witha solution of 91-3 (291 mg, 0.87 mmol) in MeCN (0.4 mL), and thenconcentrated at low pressure. The residue was purified on a silica gelcolumn (75% EA in PE)) to give 91-5 (300 mg, 86%) as a white solid.

Compound 91-5 (300 mg, 0.25 mmol) was treated with CH₃COOH (5 mL, 80%),and stirred at 50° C. for 3 h. The mixture was diluted with EA. Thesolution was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated at low pressure. The residue was purified by silica gelcolumn chromatography (67% EA in PE) to give crude compound 91, whichwas purified by HPLC. The product was dried by lyophilization to givecompound 91 (30 mg, 18.5%) as a white solid. ESI-LCMS: m/z 643 [M+H]⁺.

Example 67

To a solution of 1,1-dimethoxycyclopentane (19.3 g, 148.52 mmol) and77-1 (10.0 g, 37.13 mmol) in DCE (100 mL) was added TsOH.H₂O (0.7 g,3.71 mmol). The mixture was stirred at 50° C. for 12 h. The mixture wasneutralized with Et₃N, and concentrated at low pressure. The residue waspurified by silica gel column chromatography (1-10% MeOH in DCM) to give77-2 (8.7 g, 70.1%) as a white solid.

Compound 77-2 (20.0 g, 0.06 mol) was coevaporated with anhydrouspyridine 3 times to remove H₂O. To an ice-cold solution of 77-2 inanhydrous pyridine (100 mL) was added TsCl (22.8 g, 0.12 mol) at 0° C.,and the mixture was stirred overnight. The reaction was monitored byLCMS and TLC. The reaction was quenched with H₂O, and the mixtureextracted with EA (3×200 mL). The solution was dried over anhydrousNa₂SO₄ and evaporated at low pressure. The residue was purified bysilica gel column chromatography (DCM: MeOH=100:1 to 15:1) to give 77-3(20.0 g, 69.0%) as a white solid.

To a solution of 77-3 (20.0 g, 0.04 mol) in acetone (200 mL) was addedNaI (31.0 g, 0.2 mol), and the mixture was heated to reflux overnight.The reaction was monitored by LCMS. The reaction was quenched with asat. Na₂S₂O₃ solution. The solution was extracted with EA (3×200 mL).The organic layer was dried over anhydrous Na₂SO₄, and evaporated at lowpressure. The residue was purified by silica gel column chromatography(DCM: MeOH=100:1 to 15:1) to give 77-4 (15.0 g, 83.3%) as a white solid.

Compound 77-4 (13.4 g, 30.16 mmol) was treated with HCOOH (80%) in H₂Oat R.T. The solution was stirred at 60° C. for 2 h. The mixture wasconcentrated at low pressure. The residue was purified by columnchromatography (1%-10% MeOH in DCM) to give 77-5 (9.1 g, 80.0%) as awhite solid.

To a solution of 77-5 (5.0 g, 13.22 mmol) in anhydrous CH₃CN/THF (50 mL,1:1, v:v) was added DBU (6.0 g, 39.66 mmol) at R.T. The solution wasstirred at 50° C. for 1.5 h. The reaction was quenched with HCOOH at 0°C., and then concentrated at low pressure. The residue was purified bycolumn chromatography (50%-70% EA in PE) to give 77-6 (3.3 g, 48.1%) asa white solid.

To an ice-cold solution of 77-6 (2.1 g, 8.39 mmol) in anhydrous MeCN (21mL) was added NIS (2.4 g, 10.49 mmol) and TEA.3HF (1.0 g, 6.29 mmol)under N₂. The mixture was stirred at R.T. for 1 h. The reaction wasquenched with sat. NaHCO₃ and sat. Na₂SO₃ solution, and extracted withEA (3×100 mL). The organic phase was dried over anhydrous Na₂SO₄, andevaporated to dryness at low pressure. The residue was purified on asilica gel column (30%-50% EA in PE) to give 77-7 (1.3 g, 39.3%) as alight yellow solid.

To a stirred solution of 77-7 (3.2 g, 8.08 mmol) in anhydrous DCM (32mL) was added DMAP (2.5 g, 20.20 mmol) and Et₃N (2.5 g, 24.24 mmol) atR.T. The mixture was treated with BzCl (3.7 g, 26.66 mmol) at 0° C. andthen stirred at R.T. overnight. The reaction was quenched with water,and extracted with EA (3×60 mL). The organic phase was concentrated atlow pressure, and the residue was purified by column chromatography(20%-30% EA in PE) to give 77-8 (1.8 g, 31.6%) as a white solid.

Bu₄NOH (8.0 g, 13.74 mL, 55% in H₂O) was adjusted to pH=3-4 with TFA,and then cooled to R.T. To a solution of 77-8 (600 mg, 0.85 mmol) in DCM(10 mL) was added the Bu₄NOH solution and m-CPBA (917 mg, 4.25 mmol,80%) at R.T. The mixture was stirred at 25° C. for 48 h and then washedwith a sat. NaHCO₃ solution. The organic layer was directly passedthrough basic Al₂O₃ column, and the solvent was concentrated at lowpressure. The residue was purified by a silica gel column (20%-30% EA inPE) to give 77-9 (123 mg, 24.3%) as a white solid.

To a solution of 77-9 (300 mg, 0.50 mmol) in EA/hexane (20 mL, 1:1, v:v)was added Lindlar catalyst (200 mg) under N₂. The mixture was stirredunder H₂ (40 Psi) at 2° C. for 1.5 h. The suspension was filtered, andthe filtrate was treated with Lindlar catalyst (200 mg) under N₂, andstirred under H₂ (40 Psi) at 25° C. for 1.5 h. The mixture was filtered,and the filtrate was concentrated at low pressure to give crude 77-10(287 mg) as a white solid.

Compound 77-10 (287 mg, 0.48 mmol) was dissolved in NH₃/MeOH (30 mL, 7M). The mixture was stirred at R.T. for 24 h under N₂ and thenconcentrated at low pressure. The residue was purified by prep-HPLC(0.1% HCOOH in water and MeCN) to give 77-11 (50 mg, 34.7% over twosteps) as a white solid. ¹H-NMR (CD₃OD, 400 MHz) δ=7.86 (d, J=8.0 Hz1H), 6.26 (s, 1H), 5.62-5.86 (m, 1H), 5.49 (d, J=17.1 Hz, 1H), 5.30 (d,J=10.5 Hz, 1H), 4.41 (d, J=19.3 Hz, 1H), 3.71-3.86 (m, 1H).

Compound 77-11 (113 mg, 0.39 mmol) was co-evaporated with toluene 3times to remove H₂O. To a stirred solution of 77-11 (113 mg, 0.39 mmol)in a mixture of MeCN (0.5 mL) and NMI (320 mg, 3.90 mmol) was added asolution of 73-C (256 mg, 0.66 mmol) in MeCN (0.5 mL) at 0° C. Themixture was stirred at R.T. overnight and then concentrated at lowpressure. The residue was purified on a silica gel column (5% MeOH inDCM) to give crude compound 77, which purified by prep-HPLC (0.1% HCOOHin water and MeCN) to give compound 77 (45 mg, 20.1%) as a white solid.ESI-MS: m/z 538.2 [M−F]⁺ ESI-MS: m/z 580.2 [M+Na]⁺.

Example 68

To a solution of 77-9 (300 mg, 0.50 mmol) in MeOH (30 mL) was added wetPd/C (300 mg, 10%) under N₂. The mixture was stirred under H₂ (1 atm) at25° C. for 1.5 h. The suspension was filtered, and then concentrated atlow pressure to give crude 78-1 (307 mg) as a white solid.

Compound 78-1 (307 mg, 0.48 mmol) was dissolved in NH₃/MeOH (30 mL, 7M). The mixture was stirred at R.T. for 24 h under N₂ then concentratedat low pressure. The residue was purified by prep-HPLC (0.1% HCOOH inwater and MeCN) to give 78-2 (30 mg, 21% over two steps) as a whitesolid.

Compound 78-2 (91 mg, 0.31 mmol) was co-evaporated with toluene 3 timesto remove H₂O. To a stirred solution of 78-2 (91 mg, 0.31 mmol) in amixture of MeCN (0.5 mL) and NMI (254 mg, 3.90 mmol) was added asolution 73-C (203 mg, 0.66 mmol) in MeCN (0.5 mL) at 0° C. The mixturewas stirred at R.T. overnight and then concentrated at low pressure. Theresidue was purified on a silica gel column (5% MeOH in DCM) to thecrude compound 78, which purified by prep-HPLC (0.1% HCOOH in water andMeCN) to give compound 78 (30 mg, 17%) as a white solid. ESI-MS: m/z540.1 [M−F]⁺.

Example 69 Additional Compounds of Formula (I)

The foregoing syntheses are exemplary and can be used as a startingpoint to prepare a large number of additional compounds. Examples ofcompounds of Formula (I) that can be prepared in various ways, includingthose synthetic schemes shown and described herein, are provided below.Those skilled in the art will be able to recognize modifications of thedisclosed syntheses and to devise routes based on the disclosuresherein; all such modifications and alternate routes are within the scopeof the claims.

Example 70 HCV Replicon Assay Cells

Huh-7 cells containing the self-replicating, subgenomic HCV repliconwith a stable luciferase (LUC) reporter were cultured in Dulbecco'smodified Eagle's medium (DMEM) containing 2 mM L-glutamine andsupplemented with 10% heat-inactivated fetal bovine serum (FBS), 1%penicillin-streptomyocin, 1% nonessential amino acids, and 0.5 mg/mLG418.

Determination of Anti-HCV Activity

Determination of 50% inhibitory concentration (EC₅₀) of compounds in HCVreplicon cells were performed by the following procedure. On the firstday, 5,000 HCV replicon cells were plated per well in a 96-well plate.On the following day, test compounds were solubilized in 100% DMSO to100× the desired final testing concentration. Each compound was thenserially diluted (1:3) up to 9 different concentrations. Compounds in100% DMSO are reduced to 10% DMSO by diluting 1:10 in cell culturemedia. The compounds were diluted to 10% DMSO with cell culture media,which were used to dose the HCV replicon cells in 96-well format. Thefinal DMSO concentration was 1%. The HCV replicon cells were incubatedat 37° C. for 72 h. At 72 h, cells were processed when the cells arestill subconfluent. Compounds that reduce the LUC signal are determinedby Bright-Glo Luciferase Assay (Promega, Madison, Wis.). % Inhibitionwas determined for each compound concentration in relation to thecontrol cells (untreated HCV replicon) to calculate the EC₅₀.

Compounds of Formula (I) are active in the replicon assay. The antiviralactivity of exemplary compounds is shown in Table 2, where ‘A’ indicatesan EC₅₀<1 μM, ‘B’ indicates an EC₅₀≧1 μM and <10 μM, and ‘C’ indicatesan EC₅₀≧10 μM and <100 μM.

TABLE 2 Compound # EC₅₀ 2 A 3 A 5 A 11 A 13 B 14 A 16 A 17 A 18 A 19 A20 A 21 A 22 A 27 C 28 A 29 C 30 A 31 A 32 A 33 A 34 A 35 A 36 A 37 A 40B 41 B 42 A 43 A 49 A 51 B 52 A 53 A 54 A 55 A 56 A 57 A 58 A 59 C 60 C61 A 62 A 66 A 67 B 70 B 73 B 77 B 79 A 80 B 81 A 83 A 84 A 85 A 86 A 87A 88 A 89 A 90 A 91 A

Example 71 NS5B Inhibition Assay

The enzyme activity of NS5B570-Con1 (Delta-21) was measured as anincorporation of tritiated NMP into acid-insoluble RNA products. Thecomplementary IRES (cIRES) RNA sequence was used as a template,corresponding to 377 nucleotides from the 3′-end of HCV (−) strand RNAof the Con-1 strain, with a base content of 21% Ade, 23% Ura, 28% Cyt,and 28% Gua. The cIRES RNA was transcribed in vitro using a T7transcription kit (Ambion, Inc.) and purified using the Qiagen RNeasymaxi kit. HCV polymerase reactions contained 50 nM NS5B570-Con1, 50 nMcIRES RNA, about 0.5 μCi tritiated NTP, 1 μM of competing cold NTP, 20mM NaCl, 40 mM Tris-HCl (pH 8.0), 4 mM dithiothreitol, and 4 mM MgCl₂.Standard reactions were incubated for 2 h at 37° C., in the presence ofincreasing concentration of inhibitor. At the end of the reaction, RNAwas precipitated with 10% TCA, and acid-insoluble RNA products werefiltered on a size exclusion 96-well plate. After washing of the plate,scintillation liquid was added and radio labeled RNA products weredetected according to standard procedures with a Trilux Topcountscintillation counter. The compound concentration at which theenzyme-catalyzed rate was reduced by 50% (IC₅₀) was calculated byfitting the data to a non-linear regression (sigmoidal). The IC₅₀ valueswere derived from the mean of several independent experiments and areshown in Table 3. Compounds of Formula (I) showed activity in thisassay. A value of ‘A’ in the table below indicates an IC₅₀ of <1 μM, avalue of ‘B’ indicates an IC₅₀≧1 μM and <10 μM, and a value of ‘C’indicates an IC₅₀ value of ≧10 μM and <100 μM.

TABLE 3 Compound # IC₅₀  6 A  7a A  7b B  9 A 12 A 15 A 26 A 28 A 38 A44 A 46 A 50 A 63 A 64 A 69 A 76 A

Example 72 Assessment of Inhibition of Mitochondrial Function

Drug-associated dysfunction of mitochondria is believed to play a rolein the etiology of the various adverse symptoms that occur in patientstreated with antiviral nucleoside/nucleotides. For this reason,evaluation of compounds for their potential to inhibit mitochondrialfunction is useful. To assess the potential for nucleotide/nucleosideanalogs to interfere with normal mitochondrial functions and exhibitmitochondrial toxicity, the following were measured: (1) the ability ofnucleotides to be incorporated by human mitochondrial RNA polymerase invitro and (2) the cellular inhibition of the synthesis of themitochondrial DNA (mtDNA)-encoded protein, cytochrome c oxidase (COX-I),relative to the nuclear DNA (nDNA)-encoded mitochondrial proteinsuccinate dehydrogenase subunit A (SDH-A) in HepG2 cells. Controlcompounds and compounds of Formula (I) were studied in these assays.

Biochemical Assay

Arnold et al. “Sensitivity of Mitochondrial Transcription and Resistanceof RNA Polymerase II Dependent Nuclear Transcription to AntiviralRibonucleosides” PLoS Pathog (2012) 8 (11): e1003030.doi:10.1371/journal.ppat.1003030, which is hereby incorporated byreference in its entirety.

Assessment of Incorporation of Nucleotides by Human Mitochondrial RNAPolymerase (HMRP)

DdRp Assay with Human Mitochondrial RNA Polymerase

The DdRp assay with human mitochondrial RNA polymerase was performedunder single turnover conditions where enzyme concentration is in excessof the primer/template. The ³³P-RNA/DNA primer/template was used at aconcentration of 100 nM, together with 320 nM enzyme. The standard 10-μLreactions were carried out at 30° C. for 1 minute with 100 μM of eachnucleotide 5′-triphosphate (NTP), 10 mM MgCl₂, 50 mM NaCl, 40 mM Tris,pH 7.5, and 1 mM DTT. The reaction was stopped by adding 20 μL offormamide loading dye containing 50 mM EDTA. RNA products were resolvedby electrophoresis on 22.5% TBE Urea polyacrylamide sequencing gels thatwere scanned using a TYPHOON PhosphorImager.

Results

As shown in both FIGS. 10 and 11, the appropriate natural nucleotideswere shown to be good substrates for incorporation by HMRP in eachtemplate. The template in FIG. 10 was designed to measure incorporationof UTP analogs. Primer/Template: (SEQ ID NO: 1) UUUUGCCGCGCC and (SEQ IDNO: 2) GGGAATGCTAGGCGCGGC. In the control water lanes, wherein nonucleotides were added, no incorporation was observed as indicated bythe lack of product band. As shown in FIG. 10, UTP and 3′-deoxy-UTP wereefficient substrates for incorporation as indicated by the prominentproduct band. The potential for misincorporation was assessed using thecontrol nucleotide CTP. As provided in FIG. 10, CTP was incorporated toa lesser extent relative to UTP. In contrast to UTP and 3′-deoxy-UTP,compounds of Formula (I) and 2′-Me-2′-F-UTP were not efficientsubstrates for incorporation by HMRP as demonstrated by the lack ofproduct band.

The template strand shown in FIG. 11 was designed to measure theincorporation of GTP analogs. Primer/Template: (SEQ ID NO: 3)UUUUGCCGCGCC and (SEQ ID NO: 4) GGGAATGCACGGCGCGGC. In the control waterlanes, no incorporation was observed as indicated by the lack of productband. GTP and 3′-deoxy-GTP were found to be efficient substrates forincorporation as demonstrated by the significant product bands. Thepotential for misincorporation was assessed using the control nucleotideATP. As shown by the lack of product band in FIG. 11, control ATP was apoor substrate for incorporation. Nucleotide analog 2′-Me-GTP (thenucleotide metabolite of monophosphate prodrug INX-0189/BMS-986094) wastested and found to be a good substrate for incorporation by HMRP asindicated by the product band. Nucleotide analog 2′-Me-2′-F-GTP(nucleotide metabolite of monophosphate prodrug GS-938) was tested andalso found to be incorporated by HMRP. In contrast, compounds of Formula(I) were not efficient substrates for incorporation into the templatestrand by HMRP as indicated by the lack of product bands in FIG. 11.

Assessment of Inhibition of Mitochondrial Protein Synthesis—Cell BasedAssay Assay Principle

MitoBiogenesis™ In Cell ELISA kits (Cat. #M5643) were obtained fromMitosciences, Oreg., USA. The MitoBiogenesis™ In Cell ELISA kit is aduplexing 96 well assay that ratios both an mtDNA and an nDNA encodedmitochondrial protein. Cells were seeded in 96 microplates and afterexposure to compounds for several cell doublings, the levels of the twomitochondrial proteins were measured simultaneously in each well. Thetwo proteins assayed were each subunits of different oxidativephosphorylation enzyme complexes, one protein being subunit I of ComplexIV (cytochrome c oxidase; COX I) that is mtDNA encoded and the otherbeing the 70 kDa subunit of Complex II (succinate dehydrogenase subunitA; SDH A) that is nDNA encoded. Complex IV includes several proteinsthat are encoded by the mtDNA while the proteins of Complex II areentirely encoded by nDNA. To control for the density of cells present atthe end of the culture period, the number of cells were assessed bystaining with Janus Green and the levels of COX I/SDH A normalized tothe final cell density.

96 Well Plate Assay Format for HepG2 Cells

On the first day, 1000 HepG2 cells per well were plated in a 96 wellplate. On the following day, compounds to be tested were solubilized in100% DMSO to 100× the desired final testing concentration. Each compoundwas serially diluted (1:3) up to 9 distinct concentrations. Compounds in100% DMSO were reduced to 10% (v/v) DMSO by diluting 1:10 in cellculture media. A 10 μL aliquot of the compounds diluted to 10% (v/v)DMSO with cell culture media was used to dose the cells in duplicate.The final DMSO concentration was 1% (v/v). Untreated cells and wellscontaining no cells were included on the plate to serve as controls.Cells were then incubated with compounds and observed for 8 days at 37°C. and 5% CO₂. Plates were processed as described below in the assayprocedure.

Batch Assay Format for HepG2 Cells

An alternate cell culture procedure was employed to test the potentialto mediate mitochondrial toxicity at higher concentrations thanachievable in the 96 well plate format. HepG2 cells were grown either inmedia/DMSO alone or in a series of compound concentrations in 15 cm²dishes or 6 well plates at an initial cell seeding density of 5×10⁶ and5×10⁴ cells/mL, respectively. Cells were then incubated and observed for8 days at 37° C. and 5% CO₂. After 8 days, the cells were harvested bytrypsinization, counted, and seeded in 96 well plates at a density of25,000 cells/well in 16 replicate wells. Cells were allowed to adhereovernight and then the plates were processed as described below in theassay procedure.

Assay Procedure

The assay was performed according to the manufacturer's instructions.Briefly, after the end of the culture period the cell culture media wasgently aspirated from the wells of the plate and replaced with 100 μL of4% (v/v) paraformaldehyde solution in phosphate buffered saline (PBS,Electron Microscopy Sciences Cat. #15713). After a 20 mins incubation atR.T., the solution was removed and the wells washed 3× with 300 μL ofPBS. After the final wash, the PBS was removed and the wells overlayedwith 100 μL PBS. The plates were then sealed and stored at 4° C. untilused. To perform the assay, the PBS overlay was removed by blotting on apaper towel and 100 μL of 0.5% (v/v) acetic acid added to each well toblock endogenous alkaline phosphatase activity. After a 5 minsincubation at R.T., the acetic acid solution was removed and the cellswashed once with 200 μL PBS. Then, 100 μL of permeabilization buffer(0.1% (v/v) Triton X 100) was added to each well. After 30 minsincubation at R.T., the permeabilization buffer was removed and eachwell was blocked with 200 μL of 2× blocking solution for 2 h at R.T. The2× blocking solution was then removed and 100 μL of primary antibodysolution containing anti COX I and anti SDH A antibodies in 1× blockingsolution was added to each well. Plates were then sealed and incubatedovernight at 4° C. The primary antibody/blocking solution was removedand the plate washed 3× with 250 μL 0.05% (v/v) Tween 20 in PBS. Then,100 μL of secondary antibody solution containing alkaline phosphatase(AP) labeled anti SDH A antibody and horseradish peroxidase (HRP)labeled anti COX I antibody was added and incubated for 1 h at R.T. Theplate was then washed 4× with 250 μL 0.05% (v/v) Tween 20 in PBS. Afterblotting the plate dry 100 μL of AP detection reagent was added to eachwell, and the plate incubated in the dark for 30 mins at R.T. Theoptical density of each well was then measured at 405 nm. The APdetection reagent was then removed and replaced with 100 μL of HRPdetection reagent, and the plate incubated in the dark for a further 30mins at R.T. The optical density of each well was then measured at 600nm. The HRP detection reagent was then removed and each well was thenstained with 50 μL of 1× Janus Green Stain for 5 mins at R.T. Afterremoval of the dye, the plates were washed 5× in ultrapure water toremove any remaining dye. The Janus Green stain was then solubilized bythe addition of 100 μL of 0.5 M HCl and incubated for 10 mins. Theoptical density of each well was then measured at 595 nm.

Data Analysis

The average of all replicate background measurements from eachexperimental condition was calculated and subtracted from theexperimental values of the same condition. The SDH A and COX I signalswere then plotted as a ratio (COX I/SDH A) and normalized to the JanusGreen staining intensity to correct for differences in cell density.

Results

Control compound d4T was tested and found not to inhibit mitochondrialprotein synthesis at concentrations up to 100 μM as shown in FIGS.12A-D. Control compound ddC was tested and found to strongly inhibitmitochondrial protein synthesis. See FIGS. 12A-D. As demonstrated inFIG. 12A, nucleoside monophosphate prodrug INX-08189/BMS-986094 (whichdelivers 2′-Me-GTP) was tested in the assay and found to stronglyinhibit mitochondrial protein synthesis. In contrast, compounds ofFormula (I) were tested and found to not inhibit mitochondrial proteinsynthesis at concentrations up to 100 μM as shown in FIGS. 12B-D.

Example 73 Combination of Compounds Combination Testing

Two or more test compounds were tested in combination with each otherusing an HCV genotype 1b HCV replicon harbored in Huh7 cells with astable luciferase (LUC) reporter. Cells were cultured under standardconditions in Dulbecco's modified Eagle's medium (DMEM; Mediatech Inc,Herndon, Va.) containing 10% heat-inactivated fetal bovine serum (FBS;Mediatech Inc, Herndon, Va.) 2 mM L-glutamine, and nonessential aminoacids (JRH Biosciences). HCV replicon cells were plated in a 96-wellplate at a density of 10⁴ cells per well in DMEM with 10% FBS. On thefollowing day, the culture medium was replaced with DMEM containingeither no compound as a control, the test compounds serially diluted inthe presence of 2% FBS and 0.5% DMSO, or a combination of compound 18with one or more test compounds serially diluted in the presence of 2%FBS and 0.5% DMSO. The cells were incubated with no compound as acontrol, with the test compounds, or the combination of compounds for 72h. The direct effects of the combination of the test compounds wereexamined using a luciferase (LUC) based reporter as determined by theBright-Glo Luciferase Assay (Promega, Madison, Wis.). Dose-responsecurves were determined for individual compounds and fixed ratiocombinations of two or more test compounds.

The method utilized for evaluating combination effects used a programcalled MacSynergy II. MacSynergy II software was kindly provided by Dr.M. Prichard (University of Michigan). The Prichard Model allows for athree-dimensional examination of drug interactions and a calculation ofthe synergy volume (units: μM²%) generated from running the repliconassay using a checkerboard combination of two or more inhibitors. Thevolumes of synergy (positive volumes) or antagonism (negative volumes)represent the relative quantity of synergism or antagonism per change inthe concentrations of the two drugs. Synergy and antagonism volumes aredefined based on the Bliss independence model. In this model, synergyvolumes of less than −25 indicate antagonistic interactions, volumes inthe −25-25 range indicate additive behavior, volumes in the 25-100 rangeindicate synergistic behavior and volumes >100 indicate strongsynergistic behavior. Determination of in vitro additive, synergisticand strongly synergistic behavior for combinations of compounds can beof utility in predicting therapeutic benefits for administering thecombinations of compounds in vivo to infected patients.

The synergy volume results for the combinations are provided in Table 4.

TABLE 4 Combination Synergy Volume Compound (μM² %) DeterminationANA-598 29.46 Synergistic (3002) HCV-796 81.72 Synergistic (3004)Ribavirin 6.77 Additive (5012) Filibuvir 23.51 Additive (3007) VX-22232.35 Synergistic (3003) BMS-790052 38.01 Synergistic (4001) VX-95032.28 Synergistic (1001) TMC-435 97.17 Synergistic (1013)

Although the foregoing has been described in some detail by way ofillustrations and examples for purposes of clarity and understanding, itwill be understood by those of skill in the art that numerous andvarious modifications can be made without departing from the spirit ofthe present disclosure. Therefore, it should be clearly understood thatthe forms disclosed herein are illustrative only and are not intended tolimit the scope of the present disclosure, but rather to also cover allmodification and alternatives coming with the true scope and spirit ofthe invention.

1. (canceled)
 2. A compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, having the structure:

wherein: B¹ is

R¹ is methyl or ethynyl; R² is hydroxyl or fluoro; R³ is hydroxyl; R⁴ ishydrogen or

R^(5A) is O⁻, OH, or an optionally substituted N-linked α-amino acidester derivative; R^(5B) is O⁻, OH, an —O-optionally substituted aryl,or

where n is 0 or 1; R^(6B) is H; R^(6C) is H or unsubstituted C₁₋₆ alkyl;R⁹, R¹⁰ and R¹¹ are independently absent or hydrogen; and Z¹ is O or S.3. The compound of claim 2, or a pharmaceutically acceptable saltthereof, wherein Z¹ is S.
 4. The compound of claim 3, or apharmaceutically acceptable salt thereof, wherein B¹ is


5. The compound of claim 4, or a pharmaceutically acceptable saltthereof, wherein R^(6C) is H or methyl.
 6. The compound of claim 4, or apharmaceutically acceptable salt thereof, wherein R¹ is methyl.
 7. Thecompound of claim 4, or a pharmaceutically acceptable salt thereof,wherein R¹ is ethynyl.
 8. The compound of claim 4, or a pharmaceuticallyacceptable salt thereof, wherein R² is hydroxyl.
 9. The compound ofclaim 4, or a pharmaceutically acceptable salt thereof, wherein R² isfluoro.
 10. The compound of claim 4, or a pharmaceutically acceptablesalt thereof, wherein R^(5A) is an optionally substituted N-linkeda-amino acid ester derivative; and R^(5B) is an —O-optionallysubstituted aryl.
 11. The compound of claim 10, or a pharmaceuticallyacceptable salt thereof, wherein the optionally substituted N-linkedα-amino acid ester derivative is N-alaninyl isopropyl ester, N-alaninylcyclohexyl ester, N-alaninyl neopentyl ester, N-valinyl isopropyl esteror N-leucinyl isopropyl ester.
 12. The compound of claim 4, or apharmaceutically acceptable salt thereof, wherein R^(5A) is O⁻ or OH;and R^(5B) is O⁻, OH or


13. The compound of claim 12, or a pharmaceutically acceptable saltthereof, wherein n is
 1. 14. The compound of claim 2, or apharmaceutically acceptable salt thereof, wherein Z¹ is O.
 15. Thecompound of claim 14, or a pharmaceutically acceptable salt thereof,wherein B¹ is


16. The compound of claim 15, or a pharmaceutically acceptable saltthereof, wherein R¹ is methyl.
 17. The compound of claim 15, or apharmaceutically acceptable salt thereof, wherein R¹ is ethynyl.
 18. Thecompound of claim 15, or a pharmaceutically acceptable salt thereof,wherein R² is hydroxyl.
 19. The compound of claim 15, or apharmaceutically acceptable salt thereof, wherein R² is fluoro.
 20. Thecompound of claim 15, or a pharmaceutically acceptable salt thereof,wherein R¹ is methyl and R² is fluoro.
 21. The compound of claim 15, ora pharmaceutically acceptable salt thereof, wherein R^(5A) is anoptionally substituted N-linked a-amino acid ester derivative; andR^(5B) is an —O-optionally substituted aryl.
 22. The compound of claim21, or a pharmaceutically acceptable salt thereof, wherein theoptionally substituted N-linked α-amino acid ester derivative isN-alaninyl isopropyl ester, N-alaninyl cyclohexyl ester, N-alaninylneopentyl ester, N-valinyl isopropyl ester or N-leucinyl isopropylester.
 23. The compound of claim 15, or a pharmaceutically acceptablesalt thereof, wherein R^(5A) is O⁻ or OH; and R^(5B) is O⁻, OH or


24. The compound of claim 23, or a pharmaceutically acceptable saltthereof, wherein n is 1.